Abstract 3696: GS-9716: A potent, selective and orally bioavailable small molecule inhibitor of MCL1 for the treatment of cancer
Authors: Matson Clinton K. , Kenney Thomas , Steiner Bart H. , Deodato Chloe R. , Yahiaoui Anella , Rubio Claudia A. , Chan Julie T. , Mollova Nevena , Keegan Kathleen S. , Venkataramani Chandrasekar 
Published: June 2022

Abstract
MCL1 is an anti-apoptotic member of the BCL2 family of proteins. These anti-apoptotic proteins prevent caspase-mediated cell apoptosis by binding to the pro-apoptotic proteins BIM, BAK and BAX, thereby inhibiting the formation of pores on the outer mitochondrial membrane. In cancer, MCL1 is upregulated to overcome such stress-induced effects, promoting cell survival, therapy resistance, and tumor progression. Here, we describe the in vitro and in vivo activity of GS-9716, a potent and selective MCL1 small molecule inhibitor that binds directly to MCL1 and induces rapid apoptosis in cancer cells by activating the mitochondrial apoptotic pathway. GS-9716 displayed potent and selective disruption of human MCL1-BIM protein dimer in vitro. In hematological and solid tumor cell line models, GS-9716 led to dose dependent reduction of MCL1-BIM and MCL1-BAK protein dimers. MCL1 protein dimer (BAK and BIM) reduction correlated with dose-dependent increases in cleaved caspase (apoptosis marker). GS-9716 potently reduced cellular viability across panels of hematological (Median GI50 = 30 nM) and breast cancer cell lines (Median GI50 = 470 nM). GS-9716 exhibits favorable pharmacokinetics properties with good oral bioavailability across species. GS-9716 dosed daily, once per week, or 7-day cycles of 2 days on/5 days off, resulted in significant tumor growth inhibition against models of multiple myeloma (H929), several TNBC cell line xenografts (HCC1187 and HCC70) and patient-derived xenografts. Also, in these models, GS-9716 demonstrated dose-dependent MCL1 protein dimer (BIM and BAK) reduction and activation of apoptosis in tumors. In addition to single agent activity, GS-9716 showed strong synergy with multiple anti-cancer therapies; robust in vitro synergy was observed with venetoclax in the AML models and as well as with paclitaxel in the TNBC models. The combination treatment of paclitaxel (dosed IV, QW) with GS-9716 (dosed orally, 2 days on/5 days off) in the TNBC HCC1187 xenograft model achieved complete tumor regression. Similar responses were also observed when GS-9716 was dosed with paclitaxel in the TNBC PDX models. GS-9716 is currently in Phase 1 clinical trial evaluating safety, tolerability and pharmacokinetics as monotherapy and in combination with anticancer therapies in adults with advanced solid tumors (NCT05006794).
Citation Format: Clinton K. Matson, Thomas Kenney, Bart H. Steiner, Chloe R. Deodato, Anella Yahiaoui, Claudia A. Rubio, Julie T. Chan, Nevena Mollova, Kathleen S. Keegan, Chandrasekar Venkataramani. GS-9716: A potent, selective and orally bioavailable small molecule inhibitor of MCL1 for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3696.