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. 2022 Mar 8;13(4):577–585. doi: 10.1021/acsmedchemlett.1c00630

Selective Macrocyclic Inhibitors of DYRK1A/B

Chelsea E Powell †,‡, John M Hatcher †,‡, Jie Jiang †,‡, Prasanna S Vatsan †,‡, Jianwei Che †,‡, Nathanael S Gray §,*
PMCID: PMC9014431  PMID: 35450378

Abstract

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Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a therapeutic target of interest due to the roles it plays in both neurological diseases and cancer. We present the development of the first macrocyclic inhibitors of DYRK1A. Initial lead inhibitor JH-XIV-68-3 (3) displayed selectivity for DYRK1A and close family member DYRK1B in biochemical and cellular assays, and demonstrated antitumor efficacy in head and neck squamous cell carcinoma (HNSCC) cell lines. However, we noted that it suffered from rapid aldehyde oxidase (AO)-mediated metabolism. To overcome this liability, we generated a derivative (JH-XVII-10 (10)), where fluorine was introduced to block the 2-position of the azaindole and render the molecule resistant to AO activity. We showed that 10 maintains remarkable potency and selectivity in biochemical and cellular assays as well as antitumor efficacy in HNSCC cell lines and improved metabolic stability. Therefore, 10 represents a promising new scaffold for developing DYRK1A-targeting chemical probes and therapeutics.

Keywords: DYRK1A, macrocyclic kinase inhibitors, selectivity, cancer, HNSCC

Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a serine/threonine kinase that is activated via autophosphorylation of a tyrosine residue in its activation loop.1 DYRK1A is a potential therapeutic target of interest in Down syndrome due to its gene being mapped to a critical region on chromosome 21.2 It is a demonstrated potential target in other neurodegenerative diseases as well, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Pick syndrome.3,4 In addition to neurodegenerative diseases, DYRK1A is a target of interest in many cancers. DYRK1A’s role in tumorigenesis is context-dependent; it can behave as either a tumor suppressor or an oncogene depending on the tumor type.5−7 While DYRK1A has been shown to contribute to antitumor activity in adult acute myeloid leukemia (AML),8 breast cancer,9 and cancer stem cell maintenance,10 its overexpression has been shown to promote tumor growth in acute lymphoblastic leukemia (ALL),11 acute megakaryoblastic leukemia (AMLK),11 glioblastomas,12,13 nonsmall-cell lung cancer (NSCLC),14 pancreatic cancer,15 and head and neck squamous cell carcinoma (HNSCC).16

When behaving as a tumor suppressor, DYRK1A has been shown to contribute to the inhibition of angiogenesis17 and induce cell cycle arrest.8 As an oncogene DYRK1A has been shown to have an even wider range of functions including sustaining cell proliferation through receptor tyrosine signaling,12,14,15 promoting cancer cell survival during DNA damage and other cellular stress,18,19 and resisting apoptosis.5,16,20 Since DYRK1A’s role in tumorigenesis is context dependent, it is critical to develop selective DYRK1A inhibitors that may serve as probes for better understanding its disease specific behavior. Additionally, DYRK1A’s known functions in major oncogenic pathways make it a potential pharmacological target either on its own, as has been shown with HNSCC,16 or in combination with other therapies, as had been shown in NSCLC.14

While there are various reports of DYRK1A inhibitors,21 the two most widely studied DYRK1A inhibitors are harmine and silmitasertib (CX-4945) (Figure 1). Harmine is a potent inhibitor of DYRK1A, leading to anticancer effects in neuroblastoma, pancreatic cancer, and HNSCC.16,22 However, it is also a potent inhibitor of monoamine oxidase (MAO)-A, which causes hallucinogenic and toxic side effects that significantly limit the therapeutic potential of harmine.4 CX-4945 was first developed as a potent and selective inhibitor of casein kinase II (CK2), and has been granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of cholangiocarcinoma.23,24 CX-4945 has since been shown to rescue Down syndrome phenotypes through DYRK1A inhibition.25 Although CX-4945 has potential as a DYRK1A targeting therapeutic, its activity against CK2 reduces its utility as a pharmacological probe. Therefore, there is an unmet clinical need for potent and selective inhibitors of DYRK1A. To address this need, here we report our efforts to develop highly potent and selective macrocyclic inhibitors of DYRK1A.

Figure 1.

Figure 1

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Structures of harmine, CX-4945, and AC15.

A recent report describing novel scaffolds that could be used as inhibitors of DYRK1A identified a nonselective azaindole kinase inhibitor AC15 (Figure 1) as a moderately potent binder of DYRK1A with a Ki of 158 nM.3 The cocrystal structure of AC15 in complex with DYRK1A revealed that the molecule adopts a U-shaped binding mode with the substituents at the 3- and 5-positions in close proximity to each other. We therefore examined a strategy whereby substituents at the 3- and 5-positions are linked with linkers of variable length and attachment type, and developed macrocyclic inhibitors of DYRK1A. We were particularly interested in macrocyclic scaffolds as they can provide diverse functionality and stereochemical complexity while maintaining a specific conformation, which can lead to high affinity and selectivity for targets.26 Macrocyclic structures are also associated with improved metabolic stability and blood-brain barrier penetration, a feature that may be of particular use for neurologically relevant targets like DYRK1A.27,28

With synthetic tractability in mind, we chose to attach pyrazole i2 at the 3-position and pyrazole i4 at the 5-postion followed by macrocyclization via an amide coupling reaction to give compound 1 (Scheme 1). We also prepared compound 2 with a slightly longer linker. Azaindole (1) was moderately potent on DYRK1A in a Z’LYTE enzyme activity assay performed at ThermoFisher with an IC50 of 158 nM (Table 1). KINOMEscan binding analysis of compound 1 against a near comprehensive panel of 456 kinases at a concentration of 1 μM revealed poor selectivity with an S score of S(1) = 0.05. We initiated a molecular modeling study with 1 using the published cocrystal structure of AC15 in complex with DYRK1A (PDB: 6EJ4) to help improve potency and selectivity.

Scheme 1. Representative Preparation of Macrocycles.

Scheme 1

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(a) Pd(PPh3)Cl2, Na2CO3 CH3CN, H2O 80 °C. (b) (i) Pd(OAc)2, CatacXium A, BPin2 Cs2CO3, 1,4-dioxane, H2O, 95 °C, (ii) NaOH, rt. (c) (i) TFA, DCM, (ii) HATU, DIEA, DMF 0 °C to rt, (iii) NaOH, H2O, MeOH, acetone, 65 °C.

Table 1. Compound Structures and Enzymatic IC50’sa.

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a

IC50’s were determined using Z’LYTE enzyme activity assays performed by SelectScreen Kinase Profiling at ThermoFisher.

The modeling study suggested that the pyrazole at the 3-position of the azaindole (right-hand side) was in close proximity to the F238 gatekeeper residue (Figure 2A). We reasoned that a trifluoromethyl group at the 3-position of this pyrazole would be able to form a π–halogen bond with F238 to increase the strength of binding and possibly improve the selectivity of this series by occupying the adjacent hydrophobic pocket. In addition, compound 1 was quite polar with a log P of 0.79, which would be offset by the installation of a trifluoromethyl group. To further improve selectivity, we decided to explore the 5-position of the pyrazole at the 5-position of the azaindole (left-hand side), since substitution at this site has been shown to improve selectivity.28 Our modeling study revealed that K174 forms a hydrogen bond with a water molecule that is 4.6 Å from the 5-position of this pyrazole. We hypothesized that a group capable of forming a hydrogen bond with this water molecule, such as a methoxy group or nitrile group would increase binding affinity as well as improve overall selectivity. Based on these observations, we designed JH-XIV-68-3 (3) and docked it into our model (Figure 2B). We found that, indeed, a nitrile group at the 5-position of left-hand side pyrazole was predicted to be in close proximity to the water molecule adjacent to K174 and could potentially form a hydrogen bond. In addition, the trifluoromethyl group at the 3-position of the right-hand side pyrazole was oriented such that it would likely form a π–halogen bond with F238. Indeed, these modifications resulted in a >10-fold improvement in potency against DYRK1A (Table 1). Our docking model also revealed a small hydrophobic pocket adjacent to the hinge binder, which we decided to probe by synthesizing 4 with a methyl group at the 2-position of the hinge binder. However, the methyl group was likely too large for the hydrophobic pocket and resulted in a 3-fold loss in potency against DYRK1A. We then prepared compounds 5 and 6 with a methoxy group instead of a nitrile group on the left-hand side pyrazole. However, the methoxy groups were likely unable to form a hydrogen bond with K174 since compound 6 was 6-fold less potent on DYRK1A.

Figure 2.

Figure 2

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(A) Docking study of 1 (magenta) using the cocrystal structure of AC15 (yellow) in complex with DYRK1A (PDB: 6EJ4). (B) Docking study of 3 (gray) using the cocrystal structure of AC15 in complex with DYRK1A. Dashed lines indicate interactions with units in Å.

We then decided to modify the hinge binder by preparing the pyrazolo pyridine 7 and the pyrrolopyrazines 8 and 9. Compound 7 was much less potent on DYRK1A likely due to the nitrogen at the 2-position being adjacent to the hydrophobic pocket of DYRK1A resulting in an unfavorable interaction. Compound 8 was slightly less potent on DYRK1A, while compound 9 was substantially less potent. We then decided to prepare JH-XVII-10 (10) with a fluorine at the 2-position. We hypothesized that the fluorine would likely increase the strength of the hydrogen bonding interactions between the hinge binder and the protein. The hydrophobic pocket was able to accommodate the fluorine, and we observed a 5-fold increase in potency against DYRK1A.

We then assessed the kinase selectivity of the two most potent compounds, 3 and 10, and observed a drastic improvement in selectivity for DYRK1A compared to 1 (Figures 3A, B, and D). In addition, dose–response analysis revealed most of the targets inhibited by >95% in the KINOMEscan binding analysis were only weakly inhibited in their corresponding enzyme activity assays with 3 having a selectivity range of 7–64-fold for DYRK1A (excluding DYRK1B) (Figure 3C). Compound 10 maintains a selectivity range of 12–540-fold for DYRK1A (excluding DYRK1B), as established by SelectScreen Kinase Profiling (ThermoFisher) (Figure 3E).

Figure 3.

Figure 3

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Kinome selectivity at 1 μM by KINOMEscan (468 kinases). (A) Compound 1 KINOMEscan showing an S-Score (5) of 0.16. (B) Compound 3 KINOMEscan showing an S-Score (5) of 0.03. (C) Compound 10 KINOMEscan showing an S-Score (3) of 0.03.(D) Compound 3 biochemical IC50’s of targets inhibited by >95% in the KINOMEscan. (E) Compound 10 biochemical IC50’s of targets inhibited by >97% in the KINOMEscan.

Satisfied with this level of selectivity for compounds 3 and 10, we chose to test their selectivity in cells. Head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and FaDu were selected for cellular kinase profiling based on their overexpression and hyperphosphorylation of DYRK1A, and their previously identified sensitivity to DYRK1A inhibition.16 We used CAL27 cells for cellular kinase profiling (KiNativ) of harmine, CX-4945, 3, and 10 at 1 μM (Figure 4). This showed that 3 was the most selective of the four compounds, with DYRK1A as the only observed target. CX-4945 was also active against CK2, as expected, and ATR. Harmine was also active against CDK8 and CDK11, which are members of the CMGC group of kinases along with DYRKs. In addition to DYRK1A, 10 was active against FAK, RSK1, 2 and 3, and JNK1, 2, and 3. Dose–response analysis of 10 using SelectScreen Kinase Profiling (ThermoFisher) revealed IC50 values of 1130 nM for JNK1, 1100 nM for JNK2, >10 000 nM for JNK3, 90 nM for FAK, 82 nM for RSK1, 80 nM for RSK2, and 61 nM for RSK3.

Figure 4.

Figure 4

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Cellular kinase profiling. KiNativ profiles of harmine, CX-4945, 3, and 10 at 1 μM after 6 h treatment in CAL27 cells.

We further examined the macrocyclic compounds’ potentials as antitumor agents in HNSCC cell lines by measuring antiproliferative activity in CAL27 and FaDu cells. siRNA knockdown of DYRK1A in these cell lines has been previously reported to result in an ∼20% decrease in cell proliferation after 72 h of growth.16 Treatments for 72 h with 10 μM 3 or 10 in CAL27 cells resulted in an ∼45% decrease in cell proliferation, which was similar to the case of harmine, while CX-4945 caused an ∼80% decrease (Figure 5). In FaDu cells, 3 decreased cell proliferation by ∼35%, 10 by ∼40%, and CX-4945 by ∼75% while harmine did not inhibit proliferation. The extent of cell growth inhibition may be higher than what was reported with DYRK1A targeting siRNA due to DYRK1B inhibition or off-target activity. Therefore, HEK293FT cells were used as a control cell line because they do not overexpress DYRK1A/B and their growth is not DYRK1A/B dependent. Both harmine and CX-4945 still showed antiproliferative effects in the HEK293T cells, while the macrocyclic compounds did not, indicating that 3 and 10 have fewer off-target effects on proliferation than harmine and CX-4945 (Figure 5 and Supporting Information Figure S1). CX-4945 was the most potent agent in all the cell lines, which may be due to CK2 inhibition as well as DYRK1A. Dose–response antiproliferative studies in these cell lines showed that 3 and 10 first induce cell growth inhibition around 1 μM, which was similar to the case of harmine (Figure S1). The shift from biochemical IC50 values in the nanomolar range to cellular effects at micromolar doses that we see with 3 and 10 is already a known phenomenon with the established DYRK1A inhibitor harmine. This may in part be due to cell permeability issues, but it is difficult to assess without further studies of DYRK1A’s function. While DYRK1A inhibition leads to proapoptotic effects in HNSCC cell lines and antitumor effects in HNSCC xenograft mouse models,16 the fact that siRNA knockdown of DYRK1A only results in a 20% loss of cell growth indicates that HNSCC cells are not as dependent on DYRK1A as some other cancer lines with identified kinase dependencies, such as NSCLC and EGFR. Therefore, the expected translatability of DYRK1A biochemical IC50’s to cellular effects will be better understood with further studies using probes like 3 and 10.

Figure 5.

Figure 5

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Antiproliferative activity in HNSCC cell lines after 72 h treatments with 10 μM compound (three biological replicates; Dunnett’s test, ****P value < 0.0001, ***P value < 0.001; Graphpad Prism 9 software).

Examination of CAL27 colony formation after 10 days of treatment showed that 3 and 10 inhibited colony formation to a similar extent as harmine at both 1 and 10 μM (Figures 6A and B). CX-4945 was a stronger inhibitor of colony formation at 10 μM but behaved similarly to 3 and 10 at 1 μM. Compound 5 inhibited colony formation slightly less than 3, 10, and harmine did at both doses, which corresponds to its observed antiproliferative activity in CAL27 cells (Figures 6A and S1).

Figure 6.

Figure 6

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Colony formation and apoptosis in CAL27 cells. (A, B) Crystal violet staining after 10 day treatment. (C, D) Immunoblot after 24 h treatment. Quantification normalized to β-actin and displayed as percentage of average DMSO.

Markers of apoptosis were examined by Western blotting after 24 h treatments in CAL27 cells. Compound 10 and CX-4945 both induced strong increases in the proapoptotic marker, cleaved PARP, at 10 μM compared to harmine at an equivalent dose (Figure 6C). CX-4945 at 10 μM led to the strongest increase in cleaved PARP, which again may be due in part to CK2 inhibition. Compound 5 also induced an increase in cleaved PARP at 10 μM, which corresponds to its inhibition of colony formation. Compound 3 did not induce a noticeable difference in cleaved PARP compared to DMSO. Expression of antiapoptotic protein BCL-xL was also measured. Compounds 6 and 10 decreased BCL-xL expression at both 1 and 10 μM, while harmine and CX-4945 did not (Figure 6C).

In order to examine the compounds’ effects on downstream DYRK1A signaling, we measured AKT and FOXO3A phosphorylation by Western blot. Previous studies have identified AKT activation in the brains of DYRK1A-overexpressing mice.29 FOXO3A phosphorylation by AKT mediates cancer cell survival, and siRNA knockdown of DYRK1A in CAL27 cells causes a decrease in p-FOXO3AS253.16,30,31 After 24 h of treatment, we observed a decrease in p-AKTS473 by CX-4945 and 10 at a dose range of 0.5 to 10 μM (Figure 6D). Compound 3 decreased p-AKTS473 expression at 5 and 10 μM, while harmine only induced a decrease at 0.5 μM. Compound 10 decreased p-FOXO3AS253 expression at a dose range of 0.5–10 μM, and compound 3 decreased p-FOXO3AS253 expression at 10 μM. CX-4945 and harmine did not affect p-FOXO3AS253 expression. Together, this indicates that 3 and 10 both have inhibitory effects on pro-tumor signaling.

With these promising results, we began investigating the in vivo pharmacokinetic (PK) profile of our lead compounds 3 and 10 in C57Bl/6 male mice (Table 2). Compound 3 was dosed at 5 mpk IV and 10 mpk PO. Unfortunately, 3 was rapidly cleared and had a very low oral bioavailability of 1.1%. Recent reports in the literature have shown azaindoles to be substrates for aldehyde oxidase (AO).32 More specifically, the 2-position on the bicyclic ring was found to be the labile site. Since compound 3 is unsubstituted at the 2-position, it is likely a substrate of AO, resulting in the observed rapid clearance. Compound 10 was dosed at 2 mpk IV and 10 mpk PO. Compound 10 exhibited much higher plasma exposure levels and lower clearance; however, the oral bioavailability was still low at only 12%. Compound 10 is likely no longer a substrate of AO since the 2- position is blocked with a fluorine resulting in the observed lower clearance level compared to compound 3.

Table 2. In Vivo Mouse Pharmacokinetic Datad.

compd administration dose (mg/kg) T1/2 (h) AUCinf (h·ng/mL) Cl (mL/min/kg) Cmax (μM) F %
3 IV 5 0.3 ± 0.1 504.9 ± 59.6 166.6 ± 20.0 n.d.  
  PO 10 2.0 ± 1.0 23.6 ± 8.1 n.d. 11.6 ± 3.4 1.1
10 IV 2 1.2 ± 0.9 8947.2 ± 4389.5 5.9 ± 5.4 34.1 ± 20.7  
  PO 10 2.4 ± 0.7 5770.3 ± 654.8 29.3 ± 4.4 6.4 ± 1.8 12.3
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d

PK studies were conducted in male C57 Bl/6 mice. All values are shown as the average and standard deviation from three animals.

In summary, we have developed a series of highly potent and selective inhibitors of DYRK1A/B using a macrocyclization approach from a nonselective kinase inhibitor AC15. Biochemical and cellular kinase profiling of 3 and 10 showed that they are potent and selective inhibitors of DYRK1A/B, with 3 achieving a cellular selectivity profile that is better than two of the lead DYRK1A probe compounds. Examining if these macrocyclic compounds could induce DYRK1A inhibitor mediated antitumor effects in HNSCC cells demonstrated that 3 and 10 behave similar to or better than harmine in terms of antiproliferative effects and decreased colony formation. 10 induced a greater amount of proapoptotic markers and inhibited known downstream DYRK1A signaling to a greater extent than harmine did. Together this indicates that 3 and 10 are promising probe compounds for a better understanding of DYRK1A’s role in tumorigenesis. These macrocyclic scaffolds present a potential new avenue for therapeutic development targeting DYRK1A. Further optimization of this chemotype, especially with regard to improving in vivo oral bioavailability, is underway and will be reported in due course.

Acknowledgments

We would like to thank Milka Kostic (Dana-Farber Cancer Institute) for helpful feedback on the manuscript.

Glossary

Abbreviations

AO

aldehyde oxidase

DYRK1A

dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A

HNSCC

head and neck squamous cell carcinoma

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00630.

  • Cellular proliferation IC50 curves, chemical characterization, and experimental details (PDF)

Author Contributions

# C.E.P. and J.M.H. contributed equally to this work. C.E.P., J.M.H., and N.S.G. conceived of the study. C.E.P. led the biological studies and performed cellular assays. J.M.H. led the medicinal chemistry effort and performed compound synthesis. J.J. performed cellular assays. P.S.V. helped with compound synthesis. J.C. performed docking studies. C.E.P and J.M.H wrote the manuscript with edits from N.S.G. All authors read and approved the manuscript.

Funding for this work was received from the National Institutes of Health (NIH): 5 F31 CA2210619-02 (C.E.P.).

The authors declare the following competing financial interest(s): Nathanael Gray is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Jengu, B2S, Inception, EoCys, Larkspur (board member) and Soltego (board member). Jianwei Che is a consultant to Soltego, Jengu, Allorion, EoCys, and equity holder for Soltego, Allorion, EoCys, and M3 bioinformatics & technology Inc. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield and Sanofi. John Hatcher is an advisor to Arbella Therapeutics.

Supplementary Material

ml1c00630_si_001.pdf (944.5KB, pdf)

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