Abstract
Targeting CDK9 has become an attractive strategy for antitumor drug development. To obtain CDK9 inhibitors with high activity and safety, we designed and synthesized a series of sulfonamide derivatives as CDK9 inhibitors based on BAY1143572, the first selective CDK9 inhibitor to enter clinical trials. Among them, the representative compound L18 was identified as a potent and selective CDK9 inhibitor (IC50 = 3.8 nM). Biological evaluation showed that L18 significantly inhibited the growth of various tumor cells and induced apoptosis by down-regulating the levels of Myc-1 and c-Myc in MV4-11 cells. Further studies showed that L18 possessed moderate metabolic properties and exhibited an in vivo safety profile superior to that of the positive control. This study provides a potential lead compound for the development of CDK9 inhibitors for cancer therapy.
Keywords: CDK9 inhibitors, sulfonamide, antitumor, Mcl-1
Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that play a pivotal role in regulating the cell cycle through the phosphorylation of key cell cycle-related proteins. This phosphorylation modulates both intracellular and extracellular signals, which in turn influence gene transcription and drive cell cycle progression. , In the tumor microenvironment, CDK expression is often dysregulated, leading to uncontrolled cell cycle progression and aberrant cell division, which contribute to cancer development. CDKs can be classified into two main groups based on their biological functions: cell cycle-related CDKs (e.g., CDK1, CDK2, CDK4, and CDK6) and transcription-related CDKs (e.g., CDK7, CDK8, CDK9, CDK12, and CDK13). Currently, several small-molecule inhibitors targeting CDK4/6 have been approved for the treatment of various cancers, including breast cancer, while additional drugs targeting CDK2, CDK7, and CDK9 are undergoing clinical trials.
The phenomenon of ″transcription addiction″ is increasingly recognized as a critical factor in the development and progression of cancer. As a result, drug development targeting transcription-related factors has garnered significant attention from researchers. CDK9, a key member of transcription-related cyclin-dependent kinases (CDKs), plays a central role in regulating RNA transcription. When bound to Cyclin T1, CDK9 forms the positive transcription elongation factor b (p-TEFb) complex, which facilitates transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II. Furthermore, CDK9 regulates the expression of key proteins, such as the antiapoptotic factor Mcl-1 (myeloid cell leukemia-1) and the oncogene c-Myc (myelocytomatosis oncogene). , Dysregulated CDK9 expression has been observed in various cancers, including acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, and brain glioma. Inhibition of CDK9 could effectively suppresses tumor cell growth by downregulating Mcl-1 protein levels. Currently, nearly 20 CDK9 inhibitors are in clinical trials, with the development of selective CDK9 inhibitors becoming a prominent trend, likely due to safety concerns. Representative CDK9 inhibitors include BAY1143572, VIP152, AZD4573, and KB-0742 (Figure ). Overall, selective targeting of CDK9 holds promise as a strategy for developing effective antitumor therapies. This study will focus on our preliminary efforts in the design and synthesis of CDK9 inhibitors.
1.
Representative selective CDK9 inhibitors.
BAY1143572, characterized by its sulfonamide functional group, was the first orally available selective CDK9 inhibitor to enter clinical trials. However, its development was discontinued due to adverse reactions, including severe neutropenia. To enhance its therapeutic window, researchers conducted further structural optimizations, resulting in the discovery of VIP152, which exhibits stronger inhibitory activity against CDK9 and is currently undergoing clinical trials. Despite this, VIP152 still faces challenges due to its narrow safety margin. This study aims to develop novel selective CDK9 inhibitors, building on BAY1143572, with improved efficacy and safety profiles.
Initially, we employed molecular docking to investigate the binding mode of BAY1143572 with the CDK9 protein (Figure ). The triazine moiety in part A of BAY1143572 forms two hydrogen bonds with the amino acid Cys106 located in the hinge region of the CDK9 protein, which is critical for the compound’s inhibitory activity against CDK9. Part B extends into the hydrophilic region, where the F atom forms a hydrogen bond with Lys48, alongside a π-π stacking interaction between the methoxy fluorophenyl group and Phe103. In addition, part C extends into the solvent region, where a π-π stacking interaction occurs between the benzene ring and Ile25, while the sulfonamide group forms a hydrogen bond with Glu107. Notably, although sulfonamide groups have increasingly attracted the attention of medicinal chemists, , no drugs containing these groups have been approved, and their safety in pharmaceutical applications remains unvalidated. Research indicates that sulfonamide groups, acting as electronic isostere of sulfonamides, have distinctive characteristics. However, the exposed hydrogen atoms might lead to toxic side effects in metabolic processes. Consequently, we hypothesized that replacing the hydrogen atom in the sulfonamide moiety with suitable substituents could lead to the development of safer CDK9 inhibitors.
2.
(A) Binding mode of BAY114357 with CDK9 protein (PDB: 3MY1); (B) sulfonamide group in BAY1143572 extending toward the solvent region of CDK9 protein.
The binding model of BAY1143572 with CDK9 reveals a large cavity near the sulfonamide group, providing an opportunity for modification. Based on this model, we introduced various structural groups to shield the exposed amine in the sulfonamide of BAY1143572. This strategy resulted in the synthesis of a new series of derivatives (Supporting Information Scheme S1), which were subsequently evaluated for their potential as CDK9 inhibitors (Table ). The introduction of saturated heterocycles or aromatic heterocycles yielded compounds L1-L3 with potent CDK9 inhibition (IC50 < 10 nM), among which the aliphatic ring-substituted compound L3 (IC50 = 0.268 μM against MOLM-13 cells) demonstrated superior antiproliferative activity compared to BAY1143573 (IC50 = 0.741 μM against MOLM-13 cells). These data indicate that the hydrogen bond interaction between the sulfonamide amine and the Glu107 residue in CDK9 is not crucial for maintaining target activity, thereby preliminarily validating the feasibility of our design. However, compared to the side chains containing heterocycles (L4, L5), the introduction of saturated aliphatic rings (L6) led to a significant reduction in target activity and antiproliferative activity. Additionally, compounds with shorter linker lengths appear to exhibit better cytotoxicity: the N-Boc-piperidine substituted compound (L7) and the N-methyl-tetrahydropyrrole substituted compound (L8) both demonstrated good tumor cell killing activity, with an IC50 value of approximately 200 nM. Subsequently, we investigated the effect of replacing the piperidine ring with different types of groups on the activity of compound L7. Interestingly, the smaller volume of cycloalkanes (L11 and L12, both IC50 = 7 nM) is more favorable to maintain the inhibitory activity of the compounds against CDK9 in comparison to the introduction of cyclohexane (L9, IC50 = 19 nM) or cyclopentane (L10, IC50 = 11 nM). However, the substitution of linear side chains (L13, L14) reduced target inhibitory activity and cell killing activity.
1. Enzyme Inhibitory Activity and Cell Proliferation Inhibitory Activity of Compounds L1–L18 .
The mean values of IC50 were measured in duplicate.
ND: No detection.
We also investigated the impact of aromatic heterocycles on activity. Encouragingly, the introduction of five-membered or six-membered aromatic heterocycles (L15-L18) further enhanced the cytotoxic activity. Among them, the compound L18 with a thiazole ring exhibited the best target activity and antiproliferative activity. Compared to BAY1143572 (IC50 = 9 nM against CDK9), L18 showed about a 2-fold increase in inhibitory activity against CDK9, achieving an IC50 value of 3.8 nM. Its antiproliferative activity in MV4-11 and MOLM-13 cells increased 6- to 8-fold, with IC50 values of 85 nM and 49 nM, respectively. Notably, the activity of L18 at both the target and cellular levels is comparable to that of the BAY1143572 derivative VIP152.
The structure of the 1,3,5-triazine ring is another key structural feature of BAY1143572. After obtaining the compound L18, we sought to evaluate the necessity of the triazine core. Examination of the binding mode of BAY1143572 with CDK9 reveals that the triazine ring occupies a cavity formed by the Phe105 residue. We hypothesized that variations in the substituents at the 5′ position of the triazine ring may significantly influence its activity. Consequently, compounds L19-L23 were synthesized by introducing different halogen groups (Scheme S2). Given that selective CDK9 inhibition is currently a primary focus in development, we also evaluated the inhibitory activities of these compounds against CDK2, which exhibits the highest homology to CDK9, as shown in Table . Assessment of compound L18’s inhibitory activity against CDK2 revealed that at a concentration of 100 nM, it exhibited only a 28.2% inhibition rate. This suggests that L18 has favorable selectivity for CDK9. The substitution with a 5-fluoropyrimidine ring (L19) preserved the CDK9 inhibitory activity and selectivity over CDK2, while the 5-Cl pyrimidine (L20) or 5-CF3 pyrimidine ring (L22) resulted in an obvious decrease in target activity. This decline was particularly notable in the latter, which almost entirely lost its inhibitory activity against CDK9 (IC50 > 100 nM). In addition, compared to compound L18 (IC50 = 0.049 μM), L19 and L20 displayed a 3- to 6-fold reduction in antiproliferative activity in MV4-11 cells, with IC50 values of 0.147 and 0.349 μM, respectively. Compound L21 essentially lost its cytotoxic activity, with IC50 > 2 μM in MV4-11 cells. Notably, the substitution of the triazine ring with a pyridine ring resulted in compound L22, which demonstrated a near-complete loss of inhibitory activity against CDK9. This underscores the critical role of the 5′ position substituents in preserving target activity. Additionally, drawing inspiration from the clinical compound VIP152, a 5-F-pyridine ring was introduced to obtain compound L23. Unfortunately, the CDK9 inhibitory activity and cytotoxicity of L23 were decreased to some extent compared to compound L18. Considering enzyme inhibitory activity, selectivity, and antiproliferative efficacy comprehensively, we selected compound L18 for further evaluation.
2. Enzyme Inhibitory Activity and Cell Proliferation Inhibitory Activity of Compounds L18–L23 .
IR: Inhibition rate.
Mean values of IC50 were measured in duplicate.
First, we evaluated the inhibitory activity of compound L18 against other CDK family members (Table ). The results showed that L18 had minimal inhibitory activity against most CDK family members, including CDK1, CDK4, CDK6, CDK7, and CDK12. Except for CDK2 (IC50 = 0.23 μM), L18 demonstrated over 100-fold selectivity against other CDK members, suggesting that L18 possesses favorable selectivity for CDKs. In order to elucidate its potent inhibitory activity against CDK9, docking studies were employed to analyze the binding mode of L18 with CDK9 (Figure ). It was found that the aminotriazine of L18 formed two hydrogen bonds with residue Cys106 of CDK9, and the methoxyfluorophenyl interacted with Lys48 in one hydrogen bond (not shown), which is similar to the binding pattern of BAY1143572 in CDK9. In addition, the thiazole ring used to enclose the sulfonamide extends into the cavity consisting of residue Lys151. Notably, the carbon group of the sulfonimide and the nitrogen atom of the thiazole ring form a new hydrogen bond with Gln27 and Lys151, respectively (Figure ), which may be crucial for the higher CDK9 inhibitory activity of L18 compared to BAY1143572.
3. CDK Kinase Inhibitory Activity of L18 .
| Kinases | IC50 (μM) |
|---|---|
| CDK1 | >1 |
| CDK2 | 0.231 |
| CDK4 | >1 |
| CDK6 | >1 |
| CDK7 | >1 |
| CDK12 | 0.492 |
| CDK9 | 0.004 |
Mean values of IC50 were measured in duplicate.
3.
(A) Binding mode of compound L18 in the ATP pocket of CDK9 (PDB: 3MY1); (B) 2D interaction mode between compound L18 and CDK9.
Subsequently, we evaluated the cytotoxic activity of L18 in different tumor cell lines (Tables and ). On the one hand, compound L18 demonstrated good inhibitory activity in multiple hematological malignancies, with most IC50 values below 0.1 μM. On the other hand, L18 also exhibited good cytotoxicity against most solid tumors, including liver cancer, breast cancer, lung cancer, and prostate cancer, with IC50 values ranging from 0.045 to 0.671 μM. Notably, the antiproliferative activity of compound L18 in HepG2 cells reached a low nanomolar level (IC50 = 0.045 μM), suggesting its potential for the treatment of hepatocellular carcinoma as well. Furthermore, we conducted a preliminary investigation of the effects of compound L18 on normal human bronchial epithelial cells (BEAS-2B) (Figure ). The results showed that L18 had moderate inhibitory activity against BEAS-2B cells, with an IC50 value of 0.402 μM, which is higher than VlP152 (lC50 = 0.137 μM), suggesting that L18 may have a better safety profile in vitro.
4. Anti-proliferative Activity of L18 in Hematoma Cell Lines.
| Cells | IC50 (μM) |
|---|---|
| MV4-11 | 0.079 |
| MOLM-13 | 0.071 |
| THP-1 | 0.062 |
| KG-1 | 0.093 |
| HL-60 | 0.175 |
Mean values of IC50 were measured three times.
5. Anti-proliferative Activity of L18 in Solid Tumor Cell Lines.
| Tissue | Cells | IC50 (μM) |
|---|---|---|
| Liver | HepG2 | 0.045 |
| Breast | MCF-7 | 0.166 |
| Prostate | 22RV1 | 0.247 |
| Lung | A549 | 0.225 |
| Colon | HCT116 | 0.282 |
| Lung | HCC827 | 0.286 |
| Breast | HCC-1937 | 0.436 |
| Colon | SW480 | 0.671 |
Mean values of IC50 were measured three times.
4.
Effect of compounds L18 and VIP152 on the proliferative activity of BEAS-2B cells.
Considering that the inhibition of CDK9 leads to a decrease in the phosphorylation levels of RNA polymerase II (p-RNAPII-ser2) and influences the expression of downstream-related proteins, we examined the effects of compound L18 on CDK9-related pathways in MV4–11 cells (Figure ). The results revealed that after 12 h of treatment, L18 significantly downregulated the levels of p-RNAPII-ser2 and reduced the protein levels of Mcl-1 and c-Myc, which were comparable to the positive control VIP152. Further experiments indicated that the regulatory effects of L18 on Mcl-1 and c-Myc proteins exhibited significant time and concentration dependence. In addition, we observed that high concentrations of L18 and VIP152 led to a decrease in CDK9 and Cyclin T1 protein expression, but the exact mechanism of this decrease requires further investigation. These results suggested that L18 could down-regulate the levels of Mcl-1 and c-Myc by suppressing the activity of CDK9, thereby effectively killing tumor cells.
5.
(A) Immunoblot in MV4-11 cells treated with indicated concentrations of compounds L18 and VIP152 for 12 h; (B) time- and dose-dependent regulation of c-Myc and Mcl-1 protein by compound L18 in MV4-11 cells.
We also investigated the effects of compound L18 on the apoptosis of hematological tumor cells. Apoptosis was assessed using flow cytometry in MV4–11 cells after 12 h of treatment with L18, and the results are shown in Figure . Compound L18 significantly induced apoptosis in MV4-11 cells, with concentrations of 0.5 μM and 1 μM resulting in 46 and 75% apoptotic cells, respectively. These effects were comparable to those of VIP152 but significantly superior to BAY1143572, aligning with the previously discussed antiproliferative experimental results. Mechanistic studies further confirmed that compound L18 effectively reduced the protein levels of poly(ADP-ribose) polymerase (PARP) and cysteine-dependent aspartate-specific protease-3 (Caspase-3), while simultaneously upregulating the expression of the cleaved substrates cleaved-PARP (Cl-PARP) and cleaved-Caspase-3 (Cl-Caspase-3), all of which are closely associated with apoptosis.
6.
(A and B) Effects of compounds L18 and VIP152 on apoptosis in MV4-11 cells after the treatment for 12 h; (C) effects of compounds L18 and VIP152 on PARP, Cl-PARP, Caspase-3, and Cl-Caspase3 in MV4-11 cells after treatment for 12 h.
We subsequently evaluated the pharmaceutical properties of compound L18 (Table ). The solubility assessment revealed that L18 exhibits a solubility of 50 μg/mL in water. In vitro metabolic characterization of L18 was also carried out using human liver microsomes. The results showed that the half-life of L18 was 124.9 min and the clearance (CL) was 27.7 (μL/min)/mg. Furthermore, in vivo pharmacokinetic (PK) studies in Sprague–Dawley (SD) rats showed that following intravenous administration of 2 mg/kg of L18 in rats, the half-life was approximately 0.6 h, with a maximum concentration of approximately 2837.6 ng/mL and a total exposure of 787.9 h·ng/mL. However, intragastric administration of 30 mg/kg of L18 resulted in a low bioavailability of approximately 7%. The above data suggest that L18 has acceptable metabolic properties and is more suitable for in vivo evaluation via intravenous administration.
7. Pharmacokinetic Parameters of L18 In Vivo.
| Parameter | T 1/2(h) | AUC0–∞(h·ng/mL) | Vz(L/kg) | Cl (L/h/kg) | C max(ng/mL) | F (%) |
|---|---|---|---|---|---|---|
| i.v. | 0.6 | 787.9 | 2.1 | 2.6 | 2837.6 | |
| i.g. | 2.5 | 811.93 | 186.2 | 464.09 | 6.87 |
Data presented was obtained by PK experiment in SD rats by intravenous administration (2 mg/kg, n = 3).
Data presented was obtained by the PK experiment in SD rats by intragastric administration (30 mg/kg, n = 3).
In addition, we conducted a preliminary assessment of the safety of L18 in Institute of Cancer Research (ICR) mice by an acute toxicity test. Considering that VIP152 is undergoing preclinical studies as a second-generation derivative of BAY1143572, we selected VIP152 as a positive control. The results showed that there were no deaths and no significant weight loss in mice injected intravenously with single doses of 50 mg/kg, 30 mg/kg, and 15 mg/kg of L18 (Figure ). In contrast, after a single intravenous injection of VIP152 at 30 mg/kg, the mice showed an obvious decrease in body weight, and 8 out of 9 mice died on the eighth day, implying a significant in vivo toxic effect of VIP152. These data suggested that L18 has a better safety profile in vivo than VIP152, which is consistent with the in vitro data.
7.
In vivo safety evaluation of compound L18 [ICR mice (n = 9) were treated with compound L18 and VIP152 by intravenous injection just on the first day, respectively]: (A) changes in body weight of mice after drug administration; (B) survival mice after drug administration.
Overall, the development of selective CDK9 inhibitors has garnered increasing attention. This study, based on the first CDK9 inhibitor to enter clinical trials, BAY1143572, involved the design and synthesis of a series of sulfonamide derivatives, ultimately identifying the selective CDK9-targeting lead compound L18 through target activity and antitumor evaluations. Compared to BAY1143572, compound L18 exhibited more significant CDK9 inhibitory activity along with tumor cell killing while maintaining good CDK9 selectivity. Biological activity assessments showed that L18 could effectively inhibit the growth of various tumor cells and induce apoptosis by down-regulating Mcl-1 and c-Myc protein levels. Evaluation of drug-like properties revealed that L18 possessed acceptable metabolic properties in vivo and in vitro. Furthermore, preliminary safety evaluations indicated that L18 had a better safety profile in vivo and in vitro compared to VIP152. Collectively, these data suggest that L18 holds promise as a lead compound for the further development of cancer treatments.
Supplementary Material
Acknowledgments
The authors acknowledge the financial support from the Postdoctoral Fellowship Program and China Postdoctoral Science Foundation (GZB20250837) and Jiangsu Distinguished Postdoctoral Program (2025ZB681).
Glossary
Abbreviations
- Caspase-3
cysteine-dependent aspartate-specific protease-3
- CDKs
cyclin-dependent kinases
- CDK9
cyclin-dependent kinase 9
- Cl-Caspase-3
cleaved-Caspase-3
- Cl-PARP
cleaved-PARP
- CL
clearance
- ICR
Institute of Cancer Research
- CTD
C-terminal domain
- c-Myc
myelocytomatosis oncogene
- Mcl-1
myeloid cell leukemia-1
- PARP
poly ADP-ribose polymerase
- PK
pharmacokinetic
- p-RNAPII-ser2
phosphorylation of RNAPII CTD at Ser2 residue
- p-TEFb
positive transcription elongation factor b
- SD
Sprague–Dawley
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00430.
Detailed synthetic procedures for compounds L1–L23; molecular docking and biological assays; NMR and HR-MS spectra (PDF)
§.
Y.L., Z.W., Y.X., and L.Y. contributed equally to this work.
Safety Statement. No unexpected or unusually high safety hazards were encountered.
The authors declare no competing financial interest.
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