Abstract 5453: Novel pan-PI3K inhibitor WX008 demonstrates significant antitumor efficacy in three xenograft tumor models

Abstract

Abstract Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. Dysregulation of the PI3K pathway is implicated in many human cancers. Thus we intended to discover novel pan-PI3K inhibitors to treat various solid tumors, such as colorectal cancer, gastric carcinoma, lung carcinoma and breast cancer, etc. Methods: We explored SAR based on a PI3K/mTOR dual inhibitor series to selectively improve the PI3K activity over that of mTOR. PI3Kα/mTOR enzymatic activity assays, MCF-7 cellular (p-AktS473) activity assay and mouse in vivo pharmacokinetic analyses were used to direct compound optimization. Compounds with superior in vitro activity and in vivo pharmacokinetic properties were then tested for in vivo antitumor efficacy in patient derived xenograft (PDX) tumor models. Results: WX008 was identified as a potent PI3K inhibitor with PI3Kα/mTOR IC50 of 0.07 nM/233 nM (selectivity 3328×) and superior MCF-7 cellular (p-AktS473) activity (IC50 of 5.91 nM). For its excellent pharmacokinetic properties WX008 was evaluated for in vivo antitumor efficacy. As results, WX008 displayed equivalent efficacy at much lower dose than BKM-120 in several PDX tumor models (Table 1). Table 1 In vivo efficacy of BKM-120 and WX008 Cmpd_IDBKM-120WX008CO-04-0032 PDX72% TGI @30 mpk86% TGI @8 mpkST-02-0013 PDX50% TGI @8 mpk 77% TGI @15 mpk53% TGI @4 mpk 90% TGI @8 mpkLU-01-0010 PDX74% TGI @30 mpk74% TGI @8 mpk Conclusions: WX008 is a novel potent pan-PI3K inhibitor with high selectivity over mTOR and inhibits tumor growth in several PDX tumor models. Citation Format: Tao Yu, Lingwei Kong, Yong Wang, Peipei Jiang, Zhe min Rong, Chang jun Wang, Jing jie Huang, Dan Yao, Yu xin Qin, Cheng de Wu, Shu hui Chen, Xin Tian, Fei Liu, Ping Dong, Zhi Lin Chen. Novel pan-PI3K inhibitor WX008 demonstrates significant antitumor efficacy in three xenograft tumor models [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 5453.