YPN005, an oral CDK7 inhibitor, exhibits a significant antitumor activity in Myc-driven cancers

Background: CDK7 plays an important role in regulating cell cycle progression and gene via activation of cell cycle kinases (CDK1, CDK2, CDK4 and CDK6) and RNA polymerase II (PolII). Recent studies indicate that the inhibition of CDK7 is an attractive strategy for the treatment of cancer by down-regulation of c-Myc expression. (Wang et al 2018) We have investigated the therapeutic efficacy of YPN005, a novel oral CDK7 inhibitor, in triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC). Methods: We evaluated antiproliferative activity of YPN005 on TNBC and HCC cells and the expression of RNA PolII and c-Myc was studied by Western Blot analyses to investigate the mechanism of action. To identify a biomarker, we examined the correlation between the level of c-Myc expression and anticancer activity of YPN005 in vitro using HCC cells. The therapeutic efficacy of YPN005 was evaluated in TNBC xenograft mouse model. Results: YPN005 significantly inhibited the proliferation of TNBC and HCC cells and IC50s was determined as 10-20 nM and 5-30 nM range, respectively. Inhibition of cell proliferation was accompanied by a decrease in the levels of RNA PolII phosphorylation and c-Myc expression. Western Blot analyses revealed that the sensitivity of HCC cells to YPN005 was correlated with the level of c-Myc expression. In vivo xenograft model of TNBC showed that oral daily administration of YPN005 for 21 days (once, and 10mg/kg) efficiently inhibited the growth of tumor. All mice survived during the dosing period without significant changes of the hematologic profiles. Conclusion: We propose that oral administration of YPN005, an orally available CDK7 inhibitor, could be a potent and attractive approach to treat the Myc overexpressing cancers. Citation Format: Kwang-Ok Lee, Jakyung Yoo, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Tae Chul Roh, Kang-Sik Seo, Hae In Rhee, Jun Hee Lee, Da-Hye Jeon, Dae Seong Lim. YPN005, an oral CDK7 inhibitor, exhibits a significant antitumor activity in Myc-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2697.