Abstract 4837: Evaluation of anticancer activities of UD-017, a novel selective and orally available CDK7 inhibitor, in blood cancers
Authors: Aga Yasuhiro , Ogi Sayaka , Onuma Kazuhiro , Sunamoto Hidetoshi , Matsushita Takashi , Ogawa Ayumi , Hasegawa toru , Kono Shigeyuki , Iwase Noriaki , Ushiyama Shigeru 
Published: August 2018

Abstract
Background: Cyclin dependent kinase 7 (CDK7) is an attractive target for anticancer drugs due to its dual roles, cell cycle regulation and gene transcription/RNA processing. We synthesized UD-017, a small-molecule, highly selective, orally active CDK7 inhibitor with a novel chemotype. In this study, we characterized anticancer effects on blood cancer cells and in vivo anticancer activity in combination with chemo- or immuno-oncology agents. Methods: We first evaluated antiproliferative activities of UD-017 on blood cancer cell lines and investigated the mechanism of activity of UD-017 using NCI-H929 cells (multiple myeloma). Apoptosis was assayed by FACS analysis of Annexin V-positive and PI negative. In vivo anticancer effect was evaluated in the mouse xenograft model with NCI-H929. We further evaluated the anticancer efficacy of UD-017 in combination with chemotherapeutics in an HCT-116 xenograft mouse model and with anti PD-1 antibody in B16F10 mouse allograft model.
Results: UD-017 strongly inhibited the proliferation of blood cancer cell lines (myeloma) with IC50s of 10-100 nM range, more broadly than other representative CDK inhibitors. In the similar assay, UD-017 showed no cytotoxicity to human peripheral blood mononuclear cells up to 10 μM. In the mechanism study, phosphorylation of RNA polymerase II c-terminal domain and expression of c-Myc were both inhibited concomitant with the antiproliferative activity in NCI-H929 cells. Significant apoptosis was induced at around 100 nM. In vivo, UD-017 almost completely inhibited the cancer growth at 50 mg/kg, q.d. for 14-day treatment in a NCI-H929 xenograft model in mice. In the combination assay in vivo, UD-017 showed a clear synergistic effect at 50 mg/kg with 5-fluorouracil (5-FU, 15 mg/kg, i.p.) without further affecting the side effects of 5-FU in HCT-116 (colorectal carcinoma) xenografted mice. Also, UD-017 (100 mg/kg) in combination with anti PD-1 antibody (250 μg/body, i.p.) showed add-on anticancer effect in B16F10-allografted mice. All of the mice in the combination group survived during the dosing period without decreasing the number of blood cells.
Conclusions: We propose UD-017 as a novel type of anticancer drug that shows complete anticancer responses in xenograft models of myeloma cancer cells, and also shows in vivo synergy in combination with chemotherapy and anti PD-1 antibody. These data support the rationale for further advancing towards clinical development.
Citation Format: Yasuhiro Aga, Sayaka Ogi, Kazuhiro Onuma, Hidetoshi Sunamoto, Takashi Matsushita, Ayumi Ogawa, toru Hasegawa, Shigeyuki Kono, Noriaki Iwase, Shigeru Ushiyama. Evaluation of anticancer activities of UD-017, a novel selective and orally available CDK7 inhibitor, in blood cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4837.