Abstract 5643: YK-2168, a potent and selective small molecule CDK9 inhibitor

Abstract Objective: Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. Specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Emerging evidence indicates that selective CDK9 inhibition may provide a therapeutic benefit against certain cancers. We disclose here for the first time a novel CDK9 inhibitor YK-2168 a clinical candidate and its preclinical results. Method: The biochemical activities of YK-2168 for CDK9, CDK1 and CDK2 were measured by literature methods (Tinggui, 2014). The in vitro anti-proliferative activity was evaluated on selected leukemia cell line MV4-11, lymphoma cell line Karpas422 and gastric carcinoma cell line SNU16. The in vivo antitumor activity of YK-2168 was evaluated in cell-derived xenograft (CDX) models of Leukemia (MV4-11) and gastric carcinoma (SNU16), YK-2168 was administered by intravenous (IV) injection. PK/PD was assessed by western blot analysis of pS2-RNA Pol ll CTD expression and cleaved caspase 3 level in the treated tumor tissues. Result: YK-2168 displayed potent selective inhibitory biochemical activity for CDK9 (IC50 : 7.5 nM), but that of CDK1 and CDK2 were modest (IC50 : 466.4 and 361.1 nM), indicative of good selectivity for CDK9. It also showed good anti-proliferative activities in tumor cell lines of different types, MV4-11 potency IC50 of 53.4 nM, Karpas422 potency IC50 of 91.1 nM, and SNU16 potency IC50 of 88.3 nM. YK-2168 showed in vivo antitumor activity in a MV4-11 CDX model with TGI =80 % @10 mpk QW (IV with 4 doses), compared with the same dose of BAY1251152 (TGI =65 % @10 mpk, QW). YK-2168 also showed good regressive antitumor activity in vivo in a SNU16 CDX model with TGI =115 % @10 mpk QW (while BAY1251152 totally inhibited growth with TGI =100%). Western blot analysis of the tumor samples showed that YK-2168 can also inhibit the expression of CDK9 downstream signal proteins and induced apoptosis in a dose-dependent manner. Conclusion: We have discovered a potent and selective small molecule CDK9 inhibitor YK-2168, which showed potent CDK9 inhibition and strong antitumor activity in both in vitro and in vivo preclinical tumor models. These results together with GLP safety results are considered highly promising and warrant moving the compound forward to clinical investigation. In fact, YK-2168 was granted phase I clinical trials in both US and China. Citation Format: Charles Z. Ding, Yingchun Liu, Wang Zhou. YK-2168, a potent and selective small molecule CDK9 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5643.