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. 2023 May 23;14(9):1629–1644. doi: 10.1039/d3md00004d

Research progress of anticancer drugs targeting CDK12

Zhijia Yan a, Yongli Du a,✉, Haibin Zhang a, Yong Zheng a, Huiting Lv a, Ning Dong a, Fang He b
PMCID: PMC10507796  PMID: 37731700

Abstract

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated CDK that plays key roles in transcription, translation, mRNA splicing, the cell cycle, and DNA damage repair. Research has identified that high expression of CDK12 in organs such as the breast, stomach, and uterus can lead to HER2-positive breast cancer, gastric cancer and cervical cancer. Inhibiting high expression of CDK12 suppresses tumor growth and proliferation, suggesting that it is both a biomarker for cancer and a potential target for cancer therapy. CDK12 inhibitors can competitively bind the CDK12 hydrophobic pocket with ATP to avoid CDK12 phosphorylation, blocking subsequent signaling pathways. The development of CDK12 inhibitors is challenging due to the high homology of CDK12 with other CDKs. This review summarizes the research progress of CDK12 inhibitors, their mechanism of action and the structure–activity relationship, providing new insights into the design of CDK12 selective inhibitors.

Structural optimization progress and future research directions of CDK12 inhibitors.graphic file with name d3md00004d-ga.jpg

1. Introduction

Cyclin-dependent kinase 12 (CDK12) is a key regulator protein of the cell cycle and is one of the cyclin-dependent kinases (CDKs) among serine/threonine kinases.1,2 CDKs are divided into two subfamilies, including cell cycle-associated CDKs (CDK1, CDK2, CDK4, and CDK6) and cell transcription-associated CDKs (CDK7–9, CDK12, and CDK13).3 CDK12 binds to cyclin K to form a complex that promotes the phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) and induces transcription.4 CDK12 plays a vital biological role in transcription, mRNA splicing, the cell cycle and DNA damage response (DDR) repair.5–8 CDK12 overexpression increases DNAJB6-L through ALE splicing which increases the aggressiveness of breast cancer cells.5 High CDK12 expression promotes IRS1-p85-ErbB receptor binding and activates the ErbB-PI3K-AKT signaling cascade for HER2-positive breast cancer development.9 CDK12 also activates ligand-mediated WNT/β-catenin signaling cascades to enhance the stemness of HER2-positive breast cancer.10 High CDK12 expression also upregulates immune inflammatory response pathways promoting cervical carcinogenesis.11 Aberrant expression of CDK12 leads to disruption of cellular metabolism and promotes cancer production and progression.12–14 Knockdown of the CDK12 gene inhibited the growth and proliferation of A2780 ovarian cancer cells and induced apoptosis of cancer cells.15 Currently, the traditional small-molecule inhibitors of CDK12 mainly include pan-inhibitors, PROTAC degraders and molecular glue degraders. Pan-inhibitors include reversible inhibitors and covalent inhibitors. Although several CDK12 inhibitors have been reported, no inhibitors are currently in clinical trials. This review summarizes the progress of research on CDK12 structure and signaling pathways, especially the development process of CDK12 inhibitors and their structure–activity relationship from the perspective of medicinal chemistry.

2. Cyclin-dependent kinase 12 (CDK12)

CDK12 is a 164 kDa kinase protein consisting of 1490 amino acids.16 CDK12 consists of the N-terminal lobe (N-lobe, about 700 amino acids), C-terminal lobe (C-lobe, about 500 amino acids), and a central Cdc2-related protein kinase domain (Cdc2-RPKD). There is a proline-rich motif (PRM) in each of the N-lobe and C-lobe. The arginine/serine-rich (RS) motif is the most important structural feature of CDK12 (Fig. 1).4 The N-lobe contains five β-strands (β1 to β5) and an αC helix connected by a “salt bridge”. The C-lobe contains seven conserved α-helices (αD to αI, αEF1/2) and a unique αK helix (Fig. 2A). Cdc2-RPKD mediates phosphorylation of the C-terminal domain of RNAP II. Although the Cys1039 residue (cysteine) in the remote loop region provides an important breakthrough for the development of covalent inhibitors (Fig. 2B),17 the development of highly selective inhibitors of CDK12 has become a major challenge due to the high homology between CDK12 and CDK13 (92% similarity in the Cdc2-RPKD) and the ability of both to form complexes with cyclin K.18,19

Fig. 1. Schematic diagram of the composition of CDK12 and CDK13 domains. RS: arginine/serine-rich motif; PRM: proline-rich motif; AR: alanine-rich motif; SR: serine-rich motif.

Fig. 1

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Fig. 2. (A) Crystal structure of the CDK12–cyclin K–ADP complex (PDB code 4NST). Cyclin K: brown. (B) Interaction of ADP with CDK12. Cys1039: pink. (C) Interaction of ADP with αC-helix. αC-helix: blue. ADP: gray. The images are generated by PyMOL 2.5.

Fig. 2

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ATP, as a switch for the catalytic activity of CDK12, enters the ATP binding pocket and generates catalytic activity by phosphorylating CDK12.20,21 The purine structure of ATP interacts with the carbonyl group of Glu814 and the amino group of Met816 to form two hydrogen bonds. Ribose forms hydrophobic interactions with surrounding residues (Leu866, Glu041, Val741, Ple813). Importantly, the phosphate structure of ATP interacts with Lys756 and Glu774 to form two hydrogen bonds that promote the formation of the CDK12–cyclin K complex by pulling the αC helix inward (Fig. 2C).4 CDK12 inhibitors can competitively bind the CDK12 hydrophobic pocket with ATP to avoid CDK12 phosphorylation, which prevents the phosphorylation and transcriptional function of the C-terminal structural domain (CTD) of RNAP II and induces cancer production and progression. CDK12 inhibitors currently reported in the literature are all ATP competitive inhibitors.22 These are classified as reversible inhibitors, covalent inhibitors, PROTAC degraders and molecular glue degraders based on the type of binding to the hydrophobic pocket.22

CDK12 and CDK13 are regulators of RNA polymerase II (Pol II) CTD phosphorylation, tightly regulating the RNA Pol II-driven transcription cycle. There is substantial redundancy between CDK12 and CDK13, and both are identified as fundamental regulators of global Pol II processivity and transcription elongation. Single inhibition of CDK12 induces DNA damage transcriptional responses associated with minimal effects on cell viability. In contrast, dual kinase inhibition results in the loss of Pol II CTD phosphorylation and greatly reduced Pol II elongation rates and processivity, and potently induces cell death, which is associated with extensive genome-wide transcriptional changes, particularly the widespread use of alternative 3′ polyadenylation sites.23

3. CDK12 and cancer

3.1. HER2-positive breast cancer

Study identifies high expression of CDK12 in HER2-positive breast cancer cells.24 The CDK12 gene is co-amplified with the HER2 gene in HER2-positive breast cancer SKBR-3 cells.25 CDK12 overexpression increases DNAJB6-L through ALE splicing, increasing the aggressiveness of breast cancer cells and promoting IRS1 expression to upregulate the ErbB-PI3K-AKT signaling pathway to indirectly activate the HER2 signaling pathway.5,9 Inhibition of high CDK12 expression inhibited migration and proliferation of HER2-positive breast cancer cells by activating PI3K-AKT signaling and restoring the therapeutic effect of lapatinib (tyrosine kinase inhibitor), suggesting that dual targeting of HER2 and CDK12 may benefit HER2-positive breast cancer patients.26 High expression of CDK12 promotes WNT ligand and IRS1 expression by enhancing transcription of Pol II CTD, and activation of the WNT/β-catenin/TCF signaling pathway promotes breast cancer stem cell (CSC) production.9 High expression of CDK12 reduces trastuzumab sensitivity by inducing the proliferation of breast cancer stem cells, and inhibition of high CDK12 expression facilitates the enhancement of the anticancer effect of trastuzumab, suggesting that CDK12 inhibition helps overcome resistance to targeted breast cancer therapy.9

3.2. CDK12 and gastric cancer

High expression of CDK12 in gastric cancer cells is closely associated with the malignant phenotype.27 KMT2C mutation and CDK12 amplification are prominent in HER2-positive gastric cancer.28 High expression of CDK12 phosphorylates PAK2 to activate the MAPK signaling pathway to promote HER2-positive gastric cancer cell growth and proliferation.29 A recent study found that procaterol (adrenergic β2 agonist) inhibited CDK12 expression and downregulated MAPK signaling to inhibit the growth of human HER2-positive gastric cancer cells.30

3.3. CDK12 and cervical cancer

Cervical cancer (CC) is one of the common malignancies in women.31 It was found that the expression of CDK12 mRNA was significantly increased in cervical cancer cells. The spatial distribution of CDK12 protein requires the mediation of karyopherinβ proteins (Kapβs). Signaling pathways confirmed that nuclear transport protein transportin 1 (TNPO1) recognizes the CDK12 proline–tyrosine (PY-NLS) motif and promotes the nuclear import and gene transcription functions of CDK12. High CDK12 expression also promotes platelet release through enhanced infiltration of tumor-associated macrophages (TAMs).11 TAMs releases platelet-derived growth factor (PDGF) to promote tumor cell survival and proliferation.32,33 Functional experiments in vitro and in vivo showed that the knockdown of CDK12 inhibited the proliferation and colony formation of cancer cells and promoted apoptosis.11

3.4. CDK12 and ovarian cancer

High-grade serous ovarian cancer (HGSOC) is one of the most common types of ovarian cancer (OC).34 Homozygous point mutations in the kinase domain of CDK12 kinase are major mutations for the generation of HGSOC.35 BRCA1 is an important protein involved in homologous recombination (HR) DNA repair in HGSOC, removing deleterious lesions from the gene.36 It was found that inhibition of CDK12 overexpression in HGSOC cells decreased BRCA1(DDR) expression, disrupted HR repair in ovarian cancer cells, and sensitized ovarian cancer cells to melphalan (antitumor agent) and veliparib (PARP inhibitor), inhibiting the growth and proliferation of ovarian cancer.37

3.5. CDK12 and cancer immunology

Biallelic inactivating mutations of CDK12 define a unique subtype of prostate cancer, which is characterized by features that are mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations.38 CDK12 loss is associated with genomic instability and focal tandem duplications (FTDs), which lead to highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. This phenomenon is more commonly observed in mCRPC and is characterized by FTDs that promote increased gene fusions and significant differential gene expression. CDK12 loss in prostate cancer is associated with increased gene fusions, neoantigen burden, and T cell infiltration. CDK12 mutant cases are characterized by fusion-induced chimeric open reading frames that result in elevated neoantigen burden and increased tumor T cell infiltration and clonal expansion. CDK12 mutant tumors not only show high immune infiltration but also evolve chemokine-mediated immune evasion mechanisms. This immunological phenotype may be influenced by the significant numbers of neoantigens produced by FTD-induced gene fusions in CDK12 mutant tumors. Despite the established complex and important roles of immunity in the development of prostate cancer, clinical trials for several classes of immunotherapeutics have produced mixed results. CDK12 mutations in prostate cancer have inherent immunogenicity, potentially indicating a subset of patients who could benefit from immunotherapy. Importantly, these mutations suggest a combination strategy of CDK12 inhibition and immune checkpoint blockade for the treatment of prostate cancer.38

A recent study found that the quantification of immunohistochemistry in pairs of primary and metastatic neoplasms indicated that CDK12, as a therapeutic target, was ubiquitously expressed in ovarian cancer.39 CDK12 inactivation disrupts genomic stability through unproportionate downregulation of “BRCAness” genes, thereby constituting a synthetic lethal interaction with DNA-damaging agents and PARP inhibitors. CDK12/13 inhibitors may cause unintended harm to the tumor-reactive immune environment while killing cancer cells, resulting in a decrease in T cell infiltration levels within tumor cells. CDK12/13 inhibitors suppress both tumor and immune cells and shed light on the future direction of drug discovery and application.39

4. Development of CDK12 inhibitors

Continuous research on the structure and biological function of CDK12 in recent years has facilitated the development of targeted CDK12 inhibitors.40 The development of highly selective small-molecule drugs targeting CDK12 has been a challenge due to the high homology CDK13.41 Proteolysis targeting chimeras (PROTACs) and molecular glue technology not only exhibit better selectivity but also have very significant advantages in enhancing inhibitory activity.42,43 Although unique cysteines (Cys1039) offer new research directions for the development of selective covalent inhibitors, no CDK12 inhibitors have been approved by the FDA.44 The following section will summarize recently reported different classes of small-molecule inhibitors of CDK12 and their optimization process to analyze the relationship between structure and inhibitory activity.

4.1. Reversible inhibitors

4.1.1. CDK12-IN-2

High-throughput screening (HTS) revealed that compound 1 had 36 times more selective inhibitory activity against CDK2 (IC50 = 10 nM) than CDK12 (IC50 = 360 nM) and almost no inhibitory activity against CDK7/8/9. To confirm the key structure of compound 1 selectivity for CDK12, docking models of compound 1 with CDK2 and CDK12 were constructed. It was found that the O atom of the sulfonamide group in compound 1 forms a hydrogen bonding interaction with the amino group of Lys89 (CDK2). Comparison of these models shows that an oxygen atom in the sulfonyl part of compound 1 can form hydrogen bonding with Lys89 of CDK2, while the corresponding amino acid position in the model of CDK12 is replaced by Gly822. This suggests the necessity to disrupt the hydrogen bonding of compound 1 to the Lys89 residue to reduce the inhibitory activity on CDK2. The overlay of the single crystal X-ray structures shows the perpendicularity of the bialyl group of compound 1 to the piperidine ring. Substitution of sulfonamide of compound 1 with tertiary amine maintains the orthogonal conformation of the molecular skeleton to obtain compound 2. The inhibitory activity of compound 2 to CDK12 (IC50 = 130 nM) is 3 times that of compound 1, and the selectivity to CDK12 is 3.6 times that of CDK2 (IC50 = 470 nM). Compound 3 was obtained by replacing the 3-cyanopyridine of compound 2 with quinazoline. The inhibitory activity of compound 3 to CDK12 (IC50 = 13 nM) is 10 times that of compound 2, but the selectivity for CDK12 is only 2 times that of CDK2 (IC50 = 24 nM). It is speculated that the acetyl group of compound 2 is the key structure for enhancing the inhibitory activity of CDK12, which has dual functions of regulating ligand conformation and forming hydrogen bonds (Fig. 3A). The crystal structure of compound 3-CDK12 (PDB 6CKX) revealed that the N atom of amino-quinazoline of compound 3 formed two hydrogen bond interactions with the amino and carboxyl groups of Met816 residue, and the O atom of acetyl group formed hydrogen bond interactions with the amino group of Asp819 residue (Fig. 3B). To further improve the selectivity to CDK12, compound 4 was obtained by substituting the benzyl group on the acetyl group of compound 3. Compound 4 exhibited 4.8-fold lower inhibitory activity for CDK12 (IC50 = 63 nM) than compound 3 and 800-fold more selectivity for CDK12 than CDK2 (IC50 > 10 000 nM). Comparison of the docking model of compound 4-CDK12 with the crystal structure of CDK2 superimposed revealed that the significant improvement in selectivity may be due to the large spatial conflict between the benzyl group and the Lys72 residue (CDK2). To improve the aqueous solubility of compound 4 while maintaining the inhibitory activity and selectivity towards CDK12, the 1-methyl pyrazole of compound 4 was substituted with the more hydrophilic 1-methyl-2-pyridone to yield compound 5 (CDK12-IN-2) (Fig. 3A).45 The inhibitory activity of CDK12-IN-2 to CDK12 (IC50 = 52 nM) is 1.2 times that of compound 4, and the selectivity to CDK12 is more than 200 times that of CDK2/7/8/9. At the same time, CDK12-IN-2, which is a strong CDK12/13 inhibitor, showed good inhibitory activity against CDK13 (IC50 = 10 nM). Importantly, CDK12-IN-2 with better permeability did not show time-dependent inhibition of CDK12. In HER2-positive breast cancer, CDK12-IN-2 inhibits Pol II CTD-Ser2 phosphorylation and growth of SKBR-3 breast cancer cells at low micromolar concentrations.45

Fig. 3. (A) Structural optimization of CDK12-IN-2, CDK12-IN-3, and CDK12-IN-E9. (B) Binding mode of compound 3 and CDK12–cyclin K (PDB code 6CKX; compound 3, cyan; CDK12, green). (C) Binding mode of compound 9 and CDK12–cyclin K (PDB code 6B3E; compound 9, pink; CDK12, green). Km*: for Km assays [ATP] ranges from 10 to 50 μM. High*: for Km assays [ATP] = 5000 μM. The images are generated by PyMOL 2.5.

Fig. 3

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4.1.2. CDK12-IN-3

Compound 6 (dinaciclib), the first ovarian cancer drug candidate in phase III clinical trials, is a pan-inhibitor of CDK12 (IC50 = 50 nM).46 On the other hand, compound 7 (SR-3029, CK1δ/ε inhibitor), exhibits similar CDK12 inhibitory activity (IC50 = 86 nM, low ATP concentrations) and is more than 1000-fold more selective for CDK12 than CDK1/2/7/9 (Fig. 3A).47 In conclusion, dinaciclib has high inhibitory activity but poor selectivity, while SR-3029 has high selectivity but poor inhibitory activity. Comparison of the crystal structure of dinaciclib-CDK2 (PDB 4KD1) with the docking model of SR-3029-CDK12 superimposed revealed that the interactions of dinaciclib and SR-3029 are highly consistent in each hydrophobic pocket. In particular, pyrazolo[1,5-a]pyrimidine (dinaciclib) and purine (SR-3029) have completely overlapping spatial positions but have different molecular stretch directions in the solvent region. Compound 8 was obtained by substituting pyridine N-oxide of compound 6 for difluorobenzimidazole of compound 7. The inhibitory activity of compound 8 to CDK12 (IC50 = 22 nM, low ATP concentrations) is 2.3 times that of compound 6, and the selectivity for CDK12 is more than 150 times that of CDK1/7. This indicates that the difluorobenzimidazole of compound 8 is the key to enhances its selectivity for CDK12. Compound 9 was obtained by substituting the pyrazolo[1,5-a]pyrimidine of compound 8 with purine. The inhibitory activity of compound 9 to CDK12 (IC50 = 14 nM, low ATP concentrations) is 1.6 times that of compound 8, and the selectivity for CDK12 is more than 23 times that of CDK1/2/7/9 (Fig. 3A). The crystal structure of compound 9-CDK12 (PDB 6B3E) revealed that the N of the purine of compound 9 forms a hydrogen bond with the amino group of Met816, while N–H forms a hydrogen bond with the carbonyl group of Met816. The N of difluorobenzimidazole forms a hydrogen bond with the hydroxyl group of Tyr815, and the N–H forms a hydrogen bond with the carboxyl group of Asp819. This suggests that the formation of hydrogen bonds is essential for enhancing CDK12 selective inhibition activity. Importantly, the ethyl (N-9) of compound 9 forms hydrophobic interactions with Phe813 and occupies the interior of the ATP purine region (Fig. 3C). The ethyl (N-9) of compound 9 is substituted with isopropyl to give compound 10 (CDK12-IN-3) (Fig. 3A).48 The inhibitory activity of CDK12-IN-3 to CDK12 (IC50 = 31 nM, at low ATP concentrations) is 2.2 times that of compound 9, and the selectivity for CDK12 is more than 86 times that of CDK1/2/7/9. It is speculated that the substitution of a larger group at the ethyl position may enhance its selectivity for CDK12. CDK12-IN-3, a highly selective CDK12 inhibitor, was found to inhibit the phosphorylation of Pol II CTD Ser2 in breast cancer MCF7 cells and to inhibit the growth of ovarian cancer OV90 cells.48

4.2. Covalent inhibitors

Comparison of the CDK7/12/13 crystal structures revealed that the cysteine (Cys1039) of CDK12 is located in the CTD (remote loop) and has similar spatial positions to residues Cys312 (CDK7) and Cys1017 (CDK13), which provides a critical strategy for the development of covalent inhibitors of CDK12.17,49 CDK12 covalent inhibitor consists of a reversible inhibitor backbone and acrylamide (warhead) whose double bond forms a covalent bond with the S–H of Cys1039, providing sustained inhibition and high selectivity.50 However, the development of covalent inhibitors still faces challenges such as high pro-electron reactivity, non-specific cytotoxicity and mutation of the target cysteine.51 Current covalent inhibitors of CDK12 include CDK12-IN-E9, MFH290, THZ531 and BSJ-01-175.

4.2.1. CDK12-IN-E9

Additional studies show that compound 11 (CDK12-IN-E9) was obtained by replacing the indole group structure of compound 9 with an acrylamide (Fig. 3A).52 CDK12-IN-E9, a covalent inhibitor of CDK12 (IC50 = 8–40 nM), whose double bond of the acrylamide may form a covalent bond with the S–H of the cysteine residues in CDK7/12/13. Experiments revealed that CDK12-IN-E9 competes with THZ1 for binding to CDK12 at low concentrations, overcoming the defect that THZ series inhibitors are prone to drug resistance as ABC protein transporter substrates. CDK12-IN-E9 binds covalently to CDK12, inhibiting cancer cell growth in THZ1-resistant MYCN-expanded neuroblastoma (THZ1R NB) cells and lung cancer cells, and is expected to be a candidate for targeting CDK12 to overcome THZ1 resistance.52

4.2.2. MFH-290

Compound 12 (SNS032) was first screened by bioTHZ1 in a competitive pull-down assay.53 SNS032 (CDK2/7/9 inhibitor) showed good inhibitory activity against CDK12 (pulldown* = 34.6%) but poor selectivity for CDK2/7/9. Comparison of the crystal structure of SNS032-CDK2 (PDB 5D1J) with the CDK12 (PDB 4NST) superimposed revealed that the N atom of the 3-aminothiazole of SNS032 forms two hydrogen bonds with the amino and carboxyl groups of the Leu83 residue (CDK2) (Fig. 4A). Importantly, piperidine toward Cys1039 exposed to the solvent residue and N–H is 8.3 Å from the S atom of Cys1039 (Fig. 4B). Compound 13 was obtained by substituting an acrylamide in the piperidine of SNS032. The inhibitory activity of compound 13 to CDK12 (pulldown* = 2.6%) was 13 times that of compound 12, but the selectivity for CDK12 was reduced. Compound 14 has a 3-aminopiperidine (S) structure largely losing its ability to target CDK12 (pulldown* = 78.2%) and had almost no inhibitory activity against CDK2/7/9 (IC50 > 10 000 nM). Compound 15 (MFH290) was obtained by changing compound 14 to (R) chirality (Fig. 4A).54 MFH290 has a strong inhibitory activity to CDK12 (pulldown* = 0%), and its selectivity for CDK12 is 5–100 times that of CDK2/7/9. Capillary electrophoresis-MS/MS confirms that the (R) chirality of compound 15 leads to the flipping of the acrylamide and forming of a covalent bond with Cys1039. This suggests that chirality is one of the important factors to improve the interaction between small-molecule inhibitors and target proteins to improve the selectivity of targeting CDK12. MFH290 saturates CDK12 at a concentration of approximately 40 nM in experiments with Jurkat T-ALL and HAP1 (near-haploid) CML lines. MFH290 (40 and 200 nM) reduces the expression of RAD51 and RAD51C at both the RNA and protein level. Pharmacokinetic studies found that MFH290 showed a short half-life and high clearance rate in mouse plasma, indicating that MFH290 will be needed to improve its in vivo stability.

Fig. 4. (A) Structural optimization of MFH-290, THZ-531, and BSJ-01-175. (B) Overlay of docking model of compound 12-CDK2 (PDB 5D1J, yellow) and crystal structure of CDK12–cyclin K (PDB code 4NST, green). (C) Overlay of docking model of compound 16-CDK7 (PDB 6XD3, brown) and crystal structure of CDK12–cyclin K. (D) Overlay of docking model of compound 18-CDK12 (PDB 5ABC, grey) and crystal structure of CDK12–cyclin K. (E) Overlay of docking model of compound 21-CDK12 (PDB 7NXK, blue) and crystal structure of CDK12–cyclin K. Pulldown*: tested using CDK12 pulldown assay. Half-life*: mouse liver microsomal half-life. The images are generated by PyMOL 2.5.

Fig. 4

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4.2.3. THZ-531

A comparison of the crystal structures of CDK12–cyclin K and CDK7–cyclin K revealed that Cys1039 of CDK12 and Cys312 of CDK7 occupied similar spatial positions. Importantly, activity tests revealed that compound 16 (THZ1), which covalently targets CDK7 (IC50 = 238 nM) of Cys312, also has better CDK12 (IC50 = 893 nM) inhibitory activity (Fig. 4A).55 Comparison of the crystal structures of THZ1-CDK7 (PDB 6XD3) and CDK12 (PDB 4NST) revealed that Met94 occupies a similar spatial position to that of Asp155. The 2-aminopyrimidine of THZ1 forms a hydrogen bond with the carbonyl group of Met94, and the indole forms a hydrogen bond with the carboxyl group of Asp155. Importantly, the acrylamide of THZ1 not only forms covalent bonds with the S–H of Cys312 but also forms hydrogen bonds with the amine group. The distance between Cys312 and Cys1039 is 6.9 Å (Fig. 4C). Therefore THZ1 was used as a starting molecule for the exploitation of CDK12 covalent inhibitors. Analogously to MFH290, compound 17 (THZ532) was obtained by substituting the benzene ring of compound 16 with (S)-3-aminopiperidine. THZ532 largely lost the ability to target CDK12 and had almost no inhibitory activity against CDK7 (IC50 > 32 000 nM). Changing the chirality of compound 17 from (S) to (R) gives compound 18 (THZ531) (Fig. 4A).50 The inhibitory activity of THZ531 to CDK12 (IC50 = 158 nM) was 5.6 times that of compound 16, and the selectivity for CDK12 is more than 50 times that of CDK7/9. Comparison of the crystal structure of THZ531–CDK12 (PDB 5ABC) and CDK12 (PDB 4NST) superimposed showed that the spatial position of THZ531 is highly consistent with that of THZ1. THZ531 maintains not only the formation of a hydrogen bond between 2-aminopyrimidine and Met816 but also the formation of a covalent bond between acrylamide and S–H of Cys1039. In particular, Cys1039 was flipped 11 Å toward the outside of the binding pocket (Fig. 4D). This confirms that it is feasible to design a covalent inhibitor of CDK12 in analogy to the covalent binding of THZ1, and the inhibitory activity and selectivity for CDK12 are further enhanced. THZ531, the first irreversible covalent inhibitor of CDK12, inhibits CDK12 phosphorylation in Jurkat cells and has a significant antiproliferative effect by inhibiting the transcription of DDR genes. THZ531 has significant synergistic effects with various androgen receptor (AR) antagonists for the treatment of prostate cancer (PCa).56 The combination of THZ531 with KU-0060648 (DNA-PK inhibitor) or olaparib (PARP inhibitor) synergistically induces apoptosis in multiple myeloma (MM) cells, which may be an effective therapeutic strategy.57 In addition, THZ531 has poor metabolic stability and high clearance in mice, making it unsuitable for in vivo studies.

4.2.4. BSJ-01-175

In order to further enhance the inhibitory activity of THZ531, further optimization of the inhibitor structure is needed for cell-based assays and animal studies. Maintaining the (R) chirality and removing the methylene dimethylamine (DMA) structure of THZ531 gives compound 19. Although compound 19 had a poor half-life (3.5 min) in mouse liver microsomes, it was 15 times more selective for CDK12 than CDK2 (IC50 = 3390 nM). Changing the chirality of compound 19 to (S) gives compound 20. Compound 20 doubled the half-life of mouse liver microsomes (7.2 min), and its inhibitory activity against CDK12 (IC50 = 87.6 nM) was slightly increased. It is hypothesized that the introduction of F atoms plays an important role in prolonging the half-life of drug metabolism in vivo. Maintaining the (R) chirality and DMA structure and linking by ether bonds gives compound 21 (BSJ-01-175) (Fig. 4A).58 Although the inhibitory activity of BSJ-01-175 against CDK12 (IC50 = 156 nM) was 1.8-fold lower than that of compound 20, it had the longest half-life (8 min) against mouse liver microsomes. Comparison of the crystal structure of BSJ-01-175-CDK12 (PDB 7NXK) and CDK12 (PDB 4NST) superimposed revealed that the spatial position of BSJ-01-175 is highly consistent with that of THZ531. THZ531 not only maintains the formation of hydrogen bonds and covalent bonds but also made Cys1039 flip 9.7 Å toward the outside of the binding pocket (Fig. 4E). BSJ-01-175 has better microsomal stability and inhibitory activity, becoming the first selective CDK12/13 covalent inhibitor with in vivo therapeutic effect, providing a new exploration for cancer therapy.

4.2.5. ZSQ836

Although THZ531 is the most selective CDK12/13 covalent inhibitor due to its acrylamide moiety warhead, the commonly used acrylamide warhead brings with it unfavorable pharmacokinetics owing to irreversibility. The development of an orally bioavailable CDK12/13 covalent compound using an innovative arsenic slug approach is highly feasible. The acrylamide functional group of THZ531 was substituted with the phenyl arsenic acid functional group to obtain compound 22 (ZSQ433).39 Molecular docking studies showed that there is a certain distance between the arsenous acid warhead of ZSQ433 and Cys1039 of CDK12. Optimization of the linker of ZSQ433 yielded compound 23 (ZSQ538, EC50 = 35 nM) with high inhibition activity (Fig. 5). Molecular docking simulations showed that the phenylarsenic acid functional group of ZSQ538 forms a covalent interaction with Cys1039 of CDK12. Comparing the binding mode of ZSQ538–CDK12 and THZ531–CDK12 (PDB 5ACB), it was found that the molecular conformations were highly consistent with the binding mode of CDK12. The Cys1039 residue did not produce a significant positional change. The dock score for ZSQ538 was −10.465, while the control dock score for THZ531 was −10.191. This indicates that ZSQ538 has stronger binding stability than THZ531. Importantly, in order to reduce cross-reactivity and potential oxidative stress, the hydroxyl group of ZSQ538 was protected with thioether to obtain compound 24 (ZSQ836, EC50 = 32 nM).39 ZSQ836 can be used as a prodrug of ZSQ538. Competitive streptavidin bead pull-down assays confirmed CDK12/13 as the primary covalent targets of ZSQ538 and ZSQ836. ZSQ836 is a potent antagonist against ovarian cancer, displaying pronounced antiproliferative and cytotoxic effects in OVCAR8, HEY, and SKOV3 cell lines. ZSQ836 is orally bioavailable and impairs tumor growth in vivo and suppresses T cell proliferation and activation.39

Fig. 5. Structural optimization of ZSQ836 and ZSQ1722. EC50*: the EC50 value describes the potency of a drug in a system, referring to the concentration of the drug required to achieve half of the maximum effect.

Fig. 5

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4.2.6. ZSQ1722

A recent study identified SOX17 as a novel lineage-survival master transcription factor that shares a co-expression pattern with PAX8 in epithelial ovarian cancer. CDK small-molecule inhibitors effectively reduced the expression of SOX17 and PAX8 to inhibit neoplastic cell viability. Based on the pharmacophore of THZ531 and compound 25 (TL13–87) and introducing arsenous warhead to obtain a series of analogs, compound 26 (ZSQ1460) and compound 27 (ZSQ1722) were obtained through chemical modification and performance testing (Fig. 5).59 Pull-down and western blot results indicated that both compounds covalently engaged CDK12 and CDK13. ZSQ1460 and ZSQ1722 produced submicromolar antitumor effects on KURAMOCHI, OVCAR4 and COV 362 cells and across ovarian cancer models that expressed SOX17 and PAX8. ZSQ1722 and its metabolites elicited effective anticancer effects in vivo with dose-standardized oral bioavailability of 5.03% and 39.04%. In summary, ZSQ1722, an oral CDK12/13 inhibitor targeting SOX17 and PAX8, can effectively inhibit ovarian cancer growth in vivo.59

4.3. PROTAC degraders

The currently known reversible inhibitors and covalent inhibitors all use the “occupancy-driven” mechanism to inhibit the activity and function of CDK12 to achieve the effect of treating diseases.60 PROTACs are heterobifunctional degraders with a warhead that binds to an E3 ligase, a ligand that binds to a target protein of interest, and a linker to connect the warhead and ligand.61 Unlike ATP competition inhibitors, proteolysis-targeting chimeras (PROTACs) can simultaneously recruit CDK12 and E3 ubiquitin ligases, and initiate ubiquitin–proteasome system (UPS) degradation of CDK12 through an “event-driven” mechanism.62–64 PROTACs have multiple advantages such as catalytic, reduced frequency of administration, being longer-lasting, etc.61 However, most PROTACs have a high molecular weight (MW), poor cell permeability and unfavorable pharmacokinetic (PK) characteristics that hinder the development of PROTACs in clinical therapy.65 Current PROTAC degraders of CDK12 include 7F, BSJ-4-116, and PP-C8.

4.3.1. 7F

Recent studies showed that compound 5 (CDK12-IN-2) not only binds tightly to the hydrophobic pocket of CDK12 (Kd = 16.2 nM) but also exhibits excellent kinome-wide selectivity. Computational modeling study suggested that the 1-methylpyridin-2(1H)-one group of compound 5 extended to the solvent-exposed area, which may be replaced by the hydrophilic piperazinyl moiety to facilitate E3 ligase ligand tethering without compromising its binding affinity. Compound 28 indeed displayed a similar binding affinity with CDK12 (Kd = 27.3 nM) to that of compound 5, indicating that it could be feasible to use the piperazinyl group in compound 5 as the E3 ligase ligand tethering site. Lenalidomide was selected as the E3 ligase ligand because of its widely adopted various PROTAC degraders. Thus, the new CDK12 PROTAC degrader compound 29 (7F) was designed by connecting compound 28 with lenalidomide through a linker (Fig. 6).66 The DC50 (degradation efficiency greater than 60%) value of 7F was 2.2 nM as determined by immunoblotting in MDA-MB-231 breast cancer cells, which was 8 times that of compound 5. Protein–protein docking and 500 ns molecular dynamics (MD) simulations were performed to predict the possible structures of the CDK12–7f–CRBN ternary complex. 7F fits nicely into the grooves between CDK12 and CRBN proteins and has a good complementary relationship. In vitro experiments showed that 7F dramatically inhibited the cell growth of MFM223 and MDA-MB-436 (BRCA-deficient TNBC cell lines) with IC50 values of 47 and 197.9 nM. At a concentration of 500 nM in MDA-MB-231 cells, 7F significantly suppressed the expression of a series of DDR genes (ATM, ATR, BRCA1 and FANCI) in a time-dependent manner, which was consistent with the results from the genetic knockdown of CDK12. The combo treatment of 7F and cisplatin (DNA synthesis inhibitor) significantly inhibited MDA-MB-231 cell proliferation. A similar synergistic effect was also found with the combination of 7F and olaparib. Significantly, 7F also efficiently degraded CDK13 (DC50 = 2.2 nM) protein in MDA-MB-231 breast cancer cells. In conclusion, 7F is the first powerful and highly selective CDK12 degrader that can be used as a valuable chemical probe for further evaluation of its therapeutic potential to target CDK12/13 in TNBC.66

Fig. 6. Structural optimization of 7F, BSJ-4-116, and PP-C8. Kd*: equilibrium dissociation constant values were calculated from the ratio of Koff to Kon; DC50*: the half maximal degradation concentration; ligand efficiency*: a useful metric for lead selection.

Fig. 6

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4.3.2. BSJ-4-116

Based on the high inhibitory activity and selectivity of THZ531 to CDK12, the analysis of the key structure of THZ531 is critical for the design of a new PROTAC degrader. Firstly, THZ531 was dissected into three fragments and profiled for CDK12 binding by induced-fit docking. The results showed that compound 30 (fragment) was considered the most efficient ligand (−0.41 ligand efficiency score, IC50 = 107 nM), indicating that using the piperidine group as an E3 ligand tethering site is feasible. Compound 31 (BSJ-4-23) was designed by connecting compound 30 with lenalidomide by a linker (Fig. 6). The inhibitory activity of BSJ-4-23 against CDK12 (IC50 = 130 nM) was 12 times higher than that of compound 30. Dose titration in Jurkat cells showed that BSJ-4-23 at 250 nM caused significant degradation of CDK12 while CDK13 protein levels were minimally affected. It is inferred that the selectivity of BSJ-4-23 for CDK12 may be attributed to the failure to form a ternary complex of CDK13–BSJ-4-23–CRBN. Comparison of the docking model of CDK12–BSJ-4-23–CRBN and CDK13–BSJ-4-23–CRBN superimposed revealed that BSJ-4-23 fit tightly in the grooves between CDK12 and CRBN proteins, inducing a complementary protein–protein interaction (PPI). In particular, Lys745 (CDK12) has a similar spatial location to that of Arg723 (CDK13). The high inhibitory activity of BSJ-4-23 against CDK12 may be due to the distance between the carboxyl group of Cys394 (CRBN) and the amine group of Lys745 within the range of hydrogen bond formation, forming a stable ternary complex. Yet the lower inhibitory activity against CDK13 may be due to the fact that Met730 (CDK13) restricts the rotation of the benzene ring of Arg723, which exacerbates the spatial site block of Cys394 with Arg723 and discourages the formation of the ternary complex. Furthermore, the molecular structure of BSJ-4-23 is extremely similar to that of compound 32 (TL12-186, multi-kinase PROTAC degrader).67 Substitution of the indole group of BSJ-4-23 for the 2-(isopropyl sulfonyl) aniline group of TL12-186 gives compound 33 (BSJ-4-116) (Fig. 6).68 The inhibitory activity of BSJ-4-116 to CDK12 (IC50 = 6 nM) was 1.5 times that of compound 31 and exhibited potent CDK12 degradation in Jurkat cells in a dose- and time-dependent manner. BSJ-4-116 significantly inhibited the phosphorylation of Pol II Ser2 and Thr4, while p-Ser5 and p-Ser7 were not inhibited. Importantly, experiments have shown that the heterozygous point mutation Ile733Val in CDK12 can lead to BSJ-4-116 drug resistance in MOLT-4 and Jurkat cells. BSJ-4-116 is the first example of resistance to a divalent degradation molecule.68

4.3.3. PP-C8

Structure-guided optimization of selected hits from an in-house library of kinase inhibitors led to the identification of N9 heteroaromatic purines. Compound 34 (SR-4835), as an analogue of this series, has high inhibitory activity against CDK12.69 SR-4835 (molecular glue, IC50 = 468 nM) was potent against phosphorylated RNAP II CTDs in competitive CDK12 kinase activity tests and degrades CDK12-cyclin K in CRBN-WT and CRBN-KO cells.70 The docking mode of SR-4835–CDK12 showed that SR-4835 interacted with CDK12 similarly to compound 9. The purine group of SR-4835 formed two hydrogen bonds with the amino and carboxyl groups of Met816, and the benzimidazole group formed two hydrogen bonds with the hydroxyl group of Tyr815 and the carboxyl group of Asp819. Importantly, the halogen-substituted benzimidazole is oriented toward the solvent region and can act as a tethering site for the E3 ligase ligand. Substituting 1-methylpyrazole in SR-4835 with isopropyl and changing the chlorine atom to an ether chain gives compound 35. The inhibitory activity of compound 35 against CDK12 (IC50 = 237 nM) was increased by 2 times. Compound 36 (PP-C8) was obtained by linking lenalidomide to compound 35 through a linker (Fig. 6).70 Although the inhibitory activity of PP-C8 against CDK12 (IC50 = 645 nM) was 2.7-fold lower than that of compound 35, no degradation of CDK13 was shown. The docking model of CDK12–PP-C8–CRBN shows that stable electrostatic interactions (four hydrogen bonds, one salt bridge) and high interface complementarity are formed between the surface residues of CDK12 and CRBN. Stability tests of the ternary complexes suggest that the selectivity of PP-C8 may be due to the ease of forming stable ternary complexes with CDK12, which facilitates the subsequent polyubiquitination–proteasomal degradation. Notably, global proteomic analysis reveals that PP-C8 is highly selective for the CDK12–cyclin K complex. PP-C8 induced remarkable downregulation of both CDK12 and cyclin K protein levels in a dose-dependent manner and downregulates the mRNA level of DDR genes. This suggests that targeting the degradation of the CDK12–cyclin K complex may be a potential cancer treatment.70

4.4. Molecular glue degrader

Notably, recent studies have found that molecular glues mediate proximity-induced protein degradation. Classical molecular glue degraders have so far been identified serendipitously.71 Molecular gels are small-molecule degraders that primarily induce or stabilize protein–protein interactions (PPIs) between an E3 ubiquitin ligase and a target protein to form a ternary complex that leads to protein ubiquitination and subsequent proteasomal degradation.72,73 The physicochemical properties of molecular glues are similar to those of traditional small-molecule drugs, and most of them fall into the range of the “rule of five”.74 Classical small-molecule inhibitors act by binding to a ligandable pocket on the target protein. In contrast, molecular glue does not require a binding pocket on the target protein but instead induces or reinforces interactions between the receptor and the target protein.75 Molecular glues expand the scope of “druggable” proteins especially for use in the development of CDK12 targeted degradation. Importantly, SR-4835 was reported as a non-covalent CDK12 inhibitor in 2019, but the latest research found that it was proved to be a molecule glue degrader of cyclin K in 2022.69,70 Molecular glue degraders of CDK12 include SR-4835, (R)-CR8, HQ461, dCeMM2, dCeMM3, dCeMM4.76

4.4.1. (R)-CR8

The researchers analyzed the correlation between an antitumor drug sensitivity database and the mRNA expression levels of 499 E3 ligase components through systematic data mining. The cytotoxicity of compound 38 ((R)-CR8) was observed to correlate with the mRNA level of DDB1 (the CUL4 adaptor protein).77–79 (R)-CR8 was obtained with compound 37 ((R)-roscovitine, CDK pan-inhibitor) as the parent compound (Fig. 7A).80,81 Importantly, the crystal structure of the DDB1–(R)-CR8–CDK12–cyclin K complex elucidated that (R)-CR8 binds to the ATP pocket of CDK12 and induces a PPI between CDK12 and DDB1 by exposure to the phenylpyridine group of the solvent (Fig. 7B). The purine group of (R)-CR8 forms two hydrogen bonds with met816, while the hydroxyl group forms a hydrogen bond with Asp819. The 2-phenylpyridine group of (R)-CR8 forms hydrophobic interactions with DDB1 (Asn907, Ile909, Arg947), which confers its molecular glue activity. Asp819 is the critical residue in the PPIs of CDK12-DDB1 that forms hydrogen bonds with both the hydroxyl group ((R)-CR8) and Arg928 (DDB1) (Fig. 7C). Crucially, the αK helix of CDK12 binds to the cleft between the DDB1 structural domains BPA and BPC, which is the signature binding site for the interaction between DDB1 and DCAFs (Fig. 7D). Compound 39 was obtained by substituting the 2-phenylpyridine group of compound 38 with 1-phenylpyrazole.82 Molecular docking of the crystal structure of compound 39 with the (R)-CR8 complex (PDB 6TD3) indicates that compound 39 interacts with CDK12 and DDB1 very similarly to (R)-CR8; in particular, 1-phenylpyrazole extends out of the ATP pocket to form a hydrophobic interaction with DDB1. Compound 39 demonstrated excellent CDK inhibition values at the enzymatic and cellular levels and, in particular, efficiently, rapidly, and specifically induced ubiquitination of cyclin K and its subsequent degradation in a proteasome-dependent manner.82 The DDB1–molecular glue–CDK12 complex essentially acts as an adaptor to recruit cyclin K to DDB1 and subsequently promotes cyclin K ubiquitination and degradation.72 This suggests that cyclin K-mediated inactivation of CDK12 emerges as an interesting new mechanism for anti-cancer drugs.

Fig. 7. CDK inhibitor acts as a molecular glue to degrade cyclin K. (A) Structural optimization of (R)-CR8 and chemical structures of dCeMM2, dCeMM3 and dCeMM4.76 (B) Cartoon representation of the crystal structure of DDB1–(R)-CR8–CDK12–cyclin K (PDB code 6TD3). (C) The binding mode of (R)-CR8 with DDB1 and CDK12. (D) The αK helix of CDK12 is deeply inside DDB1 with better flexibility. DDB1, yellow; CDK12, green; cyclin K, brown; (R)-CR8, cyan; αK, red. The images are generated by PyMOL 2.5.

Fig. 7

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4.4.2. HQ461

Concurrently, compound 40 (HQ461, DC50 = 132 nM) was found to act as a novel molecular glue between CDK12 and DDB1.83 HQ461 was originally identified as a cytotoxic compound through phenotype-based high-throughput small-molecule screening (HTS) (Fig. 7A). Chemical genetics in combination with biochemical reconstitution confirmed that the mode of action of HQ461 is similar to that of (R)-CR8. HQ461 binds to the ATP pocket of CDK12 and interacts with DDB1 to form a complex that functions as a substrate-specific receptor for the E3 ubiquitin ligase complex DDB1–CUL4–RBX1, triggering polyubiquitination and degradation of cyclin K. The 5-methylthiazol-2-amine group of HQ461 was identified to be an important pharmacodynamic group for the degradation potency. Compound 41 (HQ005, DC50 = 41 nM) was obtained by replacing the methyl group of HQ461 with a hydroxymethyl group, and the degradation activity was improved by 3.2 times (Fig. 7A).83 This speculates that the hydroxyl group of HQ005 may form hydrogen bond interactions with residues of the structural domain of CDK12 kinase.

5. Conclusions

This review summarizes the important role of CDK12 in human cancer and the research progress of its inhibitors. CDK12 is one of the transcription-related CDKs that form a complex with cyclin K to produce a catalytic effect. High expression of CDK12 promotes WNT/β-catenin, ErbB-PI3K-AKT, MAPK, and DDR signaling pathways, facilitating the emergence and development of cancers such as breast, gastric, cervical, and ovarian cancers. Collectively, CDK12 is not only a biomarker but also a potential therapeutic target for cancer, and the exploitation of highly selective CDK12 inhibitors offers new strategies for cancer treatment.

All inhibitors discussed in this review occupy the ATP binding pocket of CDK12 and extend towards the entrance of the hydrophobic pocket. In particular, aromatic heterocycles (N atoms) occupy the purine region forming two hydrogen bonds with Met816, fixing the inhibitor in a central position within the pocket, and heterocycles (e.g. indole) occupy the ribose region and form hydrophobic interactions with surrounding residues (Leu866, Glu041, Val741 and Ple813) to enhance binding stability. Reversible inhibitors significantly increased the inhibitory activity of CDK12 by forming hydrogen bonds. Covalent inhibitors produced sustained inhibition of CDK12 by forming a binary complex (inhibitor–CDK12) through the formation of a covalent bond between acrylamide and Cys1039. PROTAC inhibitors combined with CDK12 and CRBN to form a ternary complex (CDK12–PROTAC–CRBN) that significantly increased the inhibitory activity and selectivity of CDK12. Molecular glue degraders selectively recruit CDK12–cyclin K to the core of DDB1–CUL4–RBX1 ligase to drive the degradation of cyclin K. In the molecular design of CDK12 inhibitors, the inhibitory activity against CDK12 can be enhanced by maintaining the vertical conformation of the molecule (compound 2) and by introducing acrylamide to form a covalent bond with 1039 residue (compound 13). The selectivity for CDK12 was enhanced by the introduction of a larger site-blocking moiety (compounds 4 and 10) taking advantage of the conformational differences between CDK12 and other CDKs. In addition, changing the molecular chirality (compounds 15 and 18) and using PROTAC technology (compounds 29 and 33) further improved the inhibitory activity and selectivity for CDK12. Activity tests revealed that the introduction of hydrophilic groups (compound 5) and halogens (compound 20) in the molecule is also an essential strategy for improving water solubility and prolonging metabolism in vivo. However, the development of selective targeting of CDK12 inhibitors remains challenging owing to the high degree of homology between CDK12 and CDKs. The development of CDK12 inhibitors has provided new insights into the development of anti-cancer drugs from multiple perspectives, including enhanced inhibitory activity and selectivity of small-molecule drugs, PROTAC and molecular glue degraders.

Author contributions

Zhijia Yan: conceptualization, data curation, formal analysis, investigation, visualization, writing – original draft, writing –review & editing. Yongli Du: funding acquisition, supervision. Haibin Zhang, Yong Zheng, Huiting Lv, Ning Dong, and Fang He: validation.

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81872744) and the Shandong Provincial Natural Science Foundation (ZR2019MH046).

Biographies

Biography

Zhijia Yan.

Zhijia Yan

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Zhijia Yan, born in Shandong, China in 1998, obtained a B.Sc. degree from Qilu University of Technology in 2020. The current research focus is drug synthesis under the supervision of Professor Yongli Du at Qilu University of Technology (Shandong Academy of Sciences).

Biography

Yongli Du.

Yongli Du

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Yongli Du, born in Shandong, China, earned a B.S. degree from Shandong Normal University in 1999 and a Ph.D. degree from the Department of Medicinal Chemistry at Shanghai Institute of Pharmaceutical Sciences, Chinese Academy of Sciences, in 2008. From 2008 to 2009, Du worked at Ruizhi Chemical Research Co., Ltd. in Shanghai, focusing on international cooperative research and development of innovative drugs. Since 2010, Du has been working in the School of Chemical and Pharmaceutical Engineering at Qilu University of Technology. The research interests of Du are focused on developing targeted innovative drugs for non-small cell lung cancer, breast cancer, and other malignant tumors. Du's research concentrates on discovering and optimizing innovative drug lead compounds, computer-aided drug design, and bioactivity evaluation.

Biography

Haibin Zhang.

Haibin Zhang

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Haibin Zhang, born in Shandong, China in 1998, earned a B.Sc. degree from Qilu University of Technology in 2020. She is engaged in research on drug synthesis under the supervision of Professor Yongli Du at Qilu University of Technology (Shandong Academy of Sciences).

Biography

Yong Zheng.

Yong Zheng

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Yong Zheng, born in Shandong, China in 1997, earned a B.Sc. degree from Qilu University of Technology in 2020. She is engaged in research on drug synthesis and organic chemistry under the supervision of Professor Yongli Du at Qilu University of Technology (Shandong Academy of Sciences).

Biography

Huiting Lv.

Huiting Lv

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Huiting Lv, born in Shandong, China in 1997, earned a B.Sc. degree from Qilu University of Technology in 2020. She is currently conducting research on drug synthesis under the guidance of Professor Yongli Du at Qilu University of Technology (Shandong Academy of Sciences).

Biography

Ning Dong.

Ning Dong

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Ning Dong was born in Shandong, China, in 1999. She received her B.Sc. degree from Dezhou College in 2021. She is engaged in research on drug synthesis under the supervision of Professor Yongli Du at Qilu University of Technology (Shandong Academy of Sciences).

Notes and references

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