LAUSR

Although activating mutations in KRAS are well recognized as a hallmark of cancer, KRAS was considered an undruggable target for over 30 years after its discovery, due to the intrinsic characteristics of KRAS proteins. The pocket of KRAS is small and has a considerably smooth and shallow surface, resulting in difficulty for small molecule to bind to the protein. Recent accelerated approval of Sotorasib (AMG 510) by FDA marked the first marketed KRASG12C inhibitor for the treatment of 2nd line KRASG12C mutation-positive NSCLC patients. Although great clinical benefits were delivered by this breakthrough medicine, intrinsic or acquired drug resistances were developed in a large portion of patients treated. HYP-2A is a new chemical entity (NCE) being developed by Sichuan Huiyu Pharmaceuticals for the treatment of KRASG12C inhibitor resistant tumors. It is an orally bioavailable, potent KRASG12C inhibitor that shows very high anti-proliferation activities in NCI-H358 cell line and various Sotorasib and Adagrasib (MRTX 849) resistant tumor cell lines in vitro and demonstrates strong in vivo efficacy in the corresponding xenograft mouse models. It inhibits NCI-H358, H358 AMGR, Mia PaCa-2, PaCa-2 AMGR, KYSE-410, and SW1573 cell lines with IC50 values range from low double-digit to single-digit nanomolar. When dosing at 10 mpk via PO, HYP-2A demonstrates significant efficacy (TGI > 75%) in SW1573 Xenograph mouse model, whereas neither Sotorasib nor Adagrasib shows any obvious efficacy at 30 mpk with TGIs less than 20% in the same experiment. Similarly, when dosing at 10 mpk via PO, HYP-2A exhibits strong efficacy (TGI > 90%) in KYSE-410 Xenograph mouse model, while neither Sotorasib nor Adagrasib shows any significant efficacy (TGI < 50%) at 30 mpk via PO dosing in the same experiment. In an acute toxicity study in rats, the maximum tolerated dose (MTD) of HYP-2A is found higher than 30 mpk. In a two-week toxicity studies in rodents, rats are found well tolerated when treated with HYP-2A via PO at 3-10mpk (QD) for 14 consecutive days. The MTD of HYP-2A is determined higher than 10 mpk. In this presentation, we will highlight the research program that leads to the discovery of HYP-2A, which is currently under IND-enabling studies. Citation Format: Shoujun Chen, Xiaoming Qiang, Haibo Wang, Yong Xiong, Ke Liu, Dengming Liao, Nan Zhong, Mingdeng Liu, Xuemei Mu, Rudan Huang, Min Li, Dengwei Gui, Meilin Huang, Yuting Chen, Yuanfu Pan, Wengang Yao, Yingte Song, Zhongbo Wang, Wenbin Wang, Jun Liu, Xingchi Yu, Zhen Liang, Yike Yuan, Zhao Ding. Discovery of HYP-2A,a 2nd- generation KRASG12C inhibitor exhibits potent in vivo efficacy in drug resistant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3448.