Abstract LB-297: <i>In vivo</i> anti-tumor efficacy of UD-017, a novel highly selective &amp; orally available CDK7 inhibitor, in colorectal cancer cells xenograft models
Authors: Yasuhiro Aga, Sayaka Ogi, Yasunori Tokunaga, Ayumi Ogawa, Kazuhiro Onuma, Takashi Matsushita, Hidetoshi Sunamoto, Toru Hasegawa, Shigeru Ushiyama
Journal: Cancer Research (2017)

Abstract Background: Cyclin dependent kinase 7 (CDK7) is an attractive target for cancer drugs due to its dual roles, cell cycle regulation &amp; gene transcription/RNA procession. Recent studies show that transcription of some oncogene is highly sensitive to inhibition of transcription such as inhibition by CDK7. The dependence of cancer cells on transcription can be therefore advantageous to CDK7 inhibitors as effective anti-cancer drugs. We synthesized a novel small molecule highly selective reversible CDK7 inhibitor, UD-017. In this study, we evaluated anti-cancer activity of UD-017 in the colorectal cancer cells, HCT-116, xenograft models in mice &amp; investigated the rationale for CDK7 inhibition as anti-cancer drugs. Experimental procedures: We first examined the pharmacokinetics profile of UD-017 after an oral administration in mice. We then evaluated the anti-tumor efficacy of UD-017 in HCT-116 xenograft models in mice. We further investigated the pharmacodynamics of UD-017 by detecting the phosphorylation levels of the retinoblastoma (cell cycle) &amp; RNA polymerase II (transcription) &amp; expression levels of c-myc in the tumor tissues in the same model after oral administration of UD-017. Results: UD-017 was identified as an orally available inhibitor of CDK7. The bioavailability was approximately 50% in BALB/c mice. In the HCT-116 xenograft model in mice, UD-017 inhibited the cancer growth by 33%, 64% &amp; 88% at 25, 50 &amp; 100 mg/kg, respectively, with clear dose-dependence by once daily administration for 14 days. Throughout the experiment, UD-017 was well tolerated with no reduction in body weights &amp; no myelosuppression. In order to evaluate the effect of UD-017 in combination with chemotherapeutics, UD-017 was administrated with 5-fluorouracil (5-FU) to HCT-116 xenografted mice with either 50 mg/kg of UD-017 alone, or 15 mg/kg ip of 5-FU alone, or in combination of UD-017 plus 5-FU. UD-017 showed clear combination effect with 5-FU without further affecting the side effects of 5-FU. Phosphorylation of the retinoblastoma was inhibited after oral administration of UD-017 time-dependently in the tumor tissues. Phosphorylation of RNA polymerase II COOH-terminal domain (CTD) was also inhibited &amp; expression of c-myc was decreased. PPAP cleavage was subsequently induced, causing apoptotic death of the cancer cells. Conclusion: We propose UD-017 as a novel type of anti-cancer drug that shows favorable oral pharmacokinetics profile &amp; complete anti-tumor responses in xenograft models of colorectal cancer cells, &amp; also shows in vivo synergy in combination with chemotherapy. These data support the rationale for further advancing towards clinical development. IND-enabling studies are in progress. Citation Format: Yasuhiro Aga, Sayaka Ogi, Yasunori Tokunaga, Ayumi Ogawa, Kazuhiro Onuma, Takashi Matsushita, Hidetoshi Sunamoto, Toru Hasegawa, Shigeru Ushiyama. In vivo anti-tumor efficacy of UD-017, a novel highly selective &amp; orally available CDK7 inhibitor, in colorectal cancer cells xenograft models [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-297. doi:10.1158/1538-7445.AM2017-LB-297