Noriaki Iwase

Abstract LB-111:In vitroanti-cancer activity of UD-017, a novel potent & highly selective CDK7 reversible inhibitor

Background: Cyclin dependent kinase 7 (CDK7) is a member of the CDK family, & has a dual function relating to the cell cycle progression & gene transcription/ RNA processing. Recently CDK7 has been emerged as an attractive target for anticancer drugs due to its dual role. We synthesized UD-017, a small molecule, highly selective CDK7 inhibitor with a novel chemotype. In this study, we characterized in vitro antiproliferative profile of UD-017 & elucidated underlying mechanism how CDK7 inhibition contributes to the antiproliferation of cancer cells. Experimental procedures: We conducted a large panel of 9 CDKs & 313 other kinases assay of UD-017 to determine its selectivity & analyzed kinetics for CDK7 enzyme inhibition. We evaluated the antiproliferative activity of UD-017 in over 100 multiple types of cancer cell lines. We then investigated the mechanism of antiproliferative activity of UD-017 using human colorectal cancer cell line, HCT-116, & human multiple myeloma cell line, NCI-H929. We also explored biomarker candidates mainly using colorectal cancer cell lines. Results: UD-017 inhibited CDK7 enzyme with an IC50 value of 16 nM, which is at least 300-fold more selective against other CDKs, CDK1 through CDK9. Inhibition of UD-017 was reversible & ATP-competitive. In a panel of 313 kinases assay, the compound inhibited CDK7 almost mono-specifically. In antiproliferative panel assays using over 100 cancer cell lines, UD-017 broadly inhibited a wide range of cancer cells from colon, breast, lung, kidney, blood, pancreas & urinary bladder cancers. Specifically, it inhibited the growth of HCT-116 & NCI-H929 with GI50 values of 29 nM and 6.8 nM, respectively. In the mechanism study of the antiproliferative activity, UD-017 inhibited phosphorylation of CDK1, CDK2 & the retinoblastoma (RB) & arrested the cell-cycle. Phosphorylation of RNA polymerase II c-terminal domain was also inhibited & expression levels of c-Myc and XIAP decreased & the cleavage of PARP increased, which were followed by significant induction of apoptosis. UD-017 showed both cell cycle arrest & induction of apoptosis. In the biomarker study, c-Myc & cyclin H showed good correlation with antiproliferative activities in 6 colorectal cancer cell lines and will be candidate biomarkers of UD-017. Conclusion: UD-017 is a potent & highly selective CDK7 inhibitor, & significantly inhibits the proliferation of human cancer cells with concomitant cell cycle arrest & induction of apoptosis. In vivo anti-tumor efficacy for UD-017 is warranted. Citation Format: Takashi Matsushita, Kazuhiro Onuma, Hidetoshi Sunamoto, Ayumi Ogawa, Sayaka Ogi, Toru Hasegawa, Shigeyuki Kono, Noriaki Iwase, Yasuhiro Aga, Shigeru Ushiyama. In vitro anti-cancer activity of UD-017, a novel potent & highly selective CDK7 reversible inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-111. doi:10.1158/1538-7445.AM2017-LB-111