Abstract 929: Discovery of novel covalent KRASG12C inhibitors that display high potency and selectivity in vitro and in vivo
Authors: Li Liansheng , Janes Matthew R. , Zhang Jingchuan , Hansen Rasmus , Peters Ulf , Guo Xin , Chen Yuching , Babbar Anjali , Firdaus Sarah J. , Feng Jun , Chen Jeffrey H. , Li Shuangwei , Li Shisheng , Thach Carol , Liu Yuan , Zarieh Ata , Kucharski Jeff M. , Wu Tao , Yu Ke , Wang Yi , Yao Yvonne , Deng Xiaohu , Zarrinkar Patrick P. , Dhanak Dashyant , Lorenzi Matthew V. , Hu-Lowe Dana , Ren Pingda , Liu Yi 
Published: August 2018

Activating mutations in KRAS have a high prevalence in human cancer. The codon 12 glycine to cysteine missense mutation (KRASG12C) is among the most common KRAS mutations, present in non-small cell lung adenocarcinoma (~15 %), colorectal adenocarcinoma (~3 %), and pancreatic adenocarcinoma (~1 %). KRASG12C was previously identified as potentially druggable by allele-specific covalent targeting of cysteine 12 near the allosteric switch II pocket (S-IIP). Building on this early work, we recently described the ARS-853 series of S-IIP KRASG12C inhibitors that covalently react with the GDP-bound state of KRASG12C, trapping KRASG12C in this inactive state. In cells, ARS-853 series compounds profoundly deplete the signaling competent GTP-bound state of KRASG12C, thereby inhibiting downstream RAS signaling. However, this series of covalent KRASG12C inhibitors exhibited modest cellular potency and/or poor pharmacokinetic properties, making them unsuitable for further evaluation of covalent KRASG12C inhibition in animal models.

We now describe in further detail the discovery and characterization of a new series of structurally distinct quinazoline based S-IIP KRASG12C inhibitors with substantially improved potency and pharmacologic properties that overcome limitations of the ARS-853 series. Through structure-guided medicinal chemistry optimization we identified compound ARS-1620, a potent, orally bioavailable covalent inhibitor of KRASG12C. The co-crystal structure of ARS-1620 covalently bound to KRASG12C reveals a distinct binding mode and additional interactions, compared to ARS-853. ARS-1620 rapidly engages KRASG12C, depletes KRASG12C-GTP in tumor cell lines, and inhibits downstream RAS signaling in a dose-dependent manner. The compound potently inhibits the growth of cell lines harboring the KRASG12C mutation with little or no effect on control cell lines. ARS-1620 demonstrates robust dose-dependent efficacy with once daily oral administration across a panel of KRASG12C-positive mouse cell line (CDX) and patient-derived (PDX) tumor xenograft models, with no response observed at all doses tested in KRASG12C-negative tumor models. The anti-tumor activity of ARS-1620 correlates with target engagement in the tumors as well as with inhibition of downstream RAS signaling. The in vivo efficacy and mutant selectivity observed with ARS-1620 across a wide range of KRASG12C mouse tumor models provides the first in vivo evidence that the S-IIP targeted approach may be a promising therapeutic strategy for patients with KRASG12C mutant cancers.

Citation Format: Liansheng Li, Matthew R. Janes, Jingchuan Zhang, Rasmus Hansen, Ulf Peters, Xin Guo, Yuching Chen, Anjali Babbar, Sarah J. Firdaus, Jun Feng, Jeffrey H. Chen, Shuangwei Li, Shisheng Li, Carol Thach, Yuan Liu, Ata Zarieh, Jeff M. Kucharski, Tao Wu, Ke Yu, Yi Wang, Yvonne Yao, Xiaohu Deng, Patrick P. Zarrinkar, Dashyant Dhanak, Matthew V. Lorenzi, Dana Hu-Lowe, Pingda Ren, Yi Liu. Discovery of novel covalent KRASG12C inhibitors that display high potency and selectivity in vitro and in vivo [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 929.