Abstract 5460: Discovery and evaluation of WX047, a potent and oral active phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor

Abstract

Abstract Background: The PI3K/AKT/mTOR signaling pathway is important in regulating cell cycle, which is directly related to cellular quiescence, proliferation and longevity. Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. Methods: By using structure-based design, the 4H-pyrido[1,2-a]pyrimidin-4-one derivative as an early lead was discovered. Further SAR studies optimized the in vitro and PK properties and led to the identification of WX047 as a potent dual inhibitor of PI3K and mTOR. Antitumor efficacy of WX047 was evaluated in the PC-3M xenograft tumor model. Results: A series of 7-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives were synthesized and evaluated for in vitro and in vivo activities. Among them, WX047 was identified as a potent dual PI3K and mTOR inhibitor with IC50 for mTOR of 19.17 nM and IC50 for PI3Kα of 3.13 nM. The cellular activity of WX047 was determined in PC-3M cells by western blot analysis of p-Akt and p-70S6K with p-Akt and p-70S6K inhibition IC50 of 16 nM and 65 nM respectively. WX047 had low clearance and high oral bioavailability relative to those of the reference compound GSK2126458. In addition, WX047 also demonstrated significant antitumor efficacy in the PC-3M xenograft tumor models (79% TGI@10mpk, PO, QD). Conclusions: WX047 has been identified as an orally active PI3K and mTOR dual inhibitor. It displays significant antitumor efficacy in the PC-3M xenograft tumor model. These support moving the compound forward to clinical investigation. Citation Format: Ning Li, Amy Guan, Lei Huang, Dongling Hao, Bo Gao, Jikui Sun, Nengyang Shih, Lingwei Kong, Peipei Jiang, Yi Li, Dan Yao, Yuxin Qin, Tao Yu, Chengde Wu, Shuhui Chen, Hongyu Yuan, Xiulian Lu. Discovery and evaluation of WX047, a potent and oral active phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor [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 5460.