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  • Several classes of small molecules that modulate

    2021-09-18

    Several classes of small molecules that modulate CDK8 activity have been reported in the patent literature (Fig. 1). A quinazoline derivative, Senexin B (SNX2-1–165, 1), showed CDK8 enzyme inhibitory activity with an IC50 value of 24–50 nM in different assay, and displayed potent, selective enzymatic inhibitory activity against CDK8 and CDK19 compared with other CDK family kinases. Furthermore, Senexin B inhibited β-catenin activity in human colon HCT-116 cancer cells, and demonstrated suppression of tumor growth in various types of in vivo model. Macrocyclic compound 2 showed CDK8 binding activity with an IC50 value of 31 nM in LanthaScreen™ assay, and also regulated transcriptional activity of β-catenin with an EC50 value of 337 nM in reporter assay with human colon HCT-116 cancer cells. Benzimidazole 3 inhibited CDK8 enzyme activity by 96% at 1μM in an ADP-GLo™ assay, and demonstrated good kinase selectivity against the CDK family (CDK1, 2, 5, 7, 9). Furthermore, 3 showed cell growth inhibitory activity against various cancer cell lines, and demonstrated tumor growth inhibition in NOD/SCID mice bearing a HCT116 tumor xenograft. Pyrazine 4 and pyridine 5, based on similar scaffolds, demonstrated enzyme inhibitory activity against CDK8 bound to cyclin C with IC50 values of 0.4 nM and 0.2 nM, respectively, in a LANCE® TR-FRET assay. Pyrrole 6 showed CDK8 enzyme inhibitory activity with an IC50 value of 7.0 nM in a LANCE® TR-FRET assay, and displayed anti-proliferative activity against human gastric AGS and colorectal HCT116 cancer AG-490 in vitro. Tricyclic compound 7 showed enzyme inhibitory activity for CDK8 with an IC50 value of 22 nM against human lung carcinoma A549 live cells in a mass spectrometry assay using the KiNativ™ platform. Recently, new mechanistic insights into the potential of CDK8 and CDK19 inhibition in cancer therapy were revealed by the discovery of high-quality small molecule probes (Type I kinase inhibitors shown in Fig. 2). The natural product Cortistatin A (8) selectively inhibited the kinase activity of the CDK8/CDK19 module in phosphorylation of the RNAP II C-terminal domain (CTD) with a CDK8 IC50 value of 12 nM in vitro, and also showed the complete selectivity against 387 kinases in cell lysate using KiNativ.™ Furthermore, Cortistatin A afforded efficacy in a disseminated human AML model, and 71% tumor volume reduction in an AML xenograft model using SET-2 cells by intraperitoneal injection. The antiproliferative and cell lineage-specific activity of Cortistatin A was caused by the enhancement of master cell fate-determining tumor-suppressor genes regulated by superenhancers. Identification of Mediator kinase substrates targeted by CDK8 and CDK19 using Cortistatin A suggested effects on pathways implicated in inflammation, growth, and metabolic regulation. In another report, an orally bioavailable small molecule CCT251545 (9), which was discovered through cell-based WNT pathway screening, was found to be a CDK8 and CDK19 selective inhibitor with an IC50 value of 7.2 nM against CDK8 in Lanthascreen TR-FRET assay. This compound was also found to show >100-fold selectivity against 291 kinases in vitro. Further optimization to improve metabolic stability lead to the identification of CCT251921 (10)2(a), 30 as a good compromise between in vitro biochemical and pharmacokinetic properties. CCT251921 showed strong affinity for CDK8 with an IC50 value of 2.3 nM in Lanthascreen TR-FRET assay, and demonstrated potent inhibition of reporter-based readouts measuring basal WNT pathway activity in human cancer cell lines LS174T (β-catenin mutant), SW480, Colo205 (APC mutant), and PA-1 (human teratocarcinoma). On the other hand, scaffold hopping from the 3,4,5-trisubstituted pyridine series lead to the identification of 4,6-disubstituted-isoquinoline derivative 11, which showed strong binding affinity for CDK8 with an IC50 value of 5.1nM in Lanthascreen TR-FRET assay. Furthermore, CCT251921 and compound 11 suppressed tumor growth in vivo in an APC-mutant SW620 human colorectal carcinoma xenograft model.