Abstract 2531: FCN-683, a novel second-generation BCL-2 inhibitor, is highly potent, selective and efficacious against clinically relevant venetoclax-resistant mutations
Authors: Lin Shu (Sophie) , Liu Hongbin , Tan Rui , Zhang Weipeng , He Chengxi , Rong Yue , Huang Zhuo , Yu Jinhua , Wang Yunling , Qi Yangli , Zhao Xingdong , Jiang Lihua , Liu Yanxin , Wang Xilei , Zou Zongyao , Sun Jing , Gao Yuwei , Wang Weibo , Guan Xiaohui , Wu Yifang 
Published: April 2023

Abstract
B-cell lymphoma 2 (BCL-2) is a member of the anti-apoptotic BCL-2 family and is dysregulated in B-cell malignancies, including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), acute myeloid leukemia (AML) and Non-Hodgkin’s lymphoma. Venetoclax (VEN), also known as ABT-199, is the only BCL-2 inhibitor approved by FDA for treating CLL/SLL and AML. VEN is a BH3-mimetic drug competitively inhibits BCL-2 by binding to the hydrophobic groove and thereby displacing proapoptotic proteins and inducing apoptosis. Despite high effectiveness of the initial treatment, most patients treated with VEN eventually relapse or develop resistance. An important resistance mechanism is acquisition of BCL-2 G101V mutation, detected in about 50% of CLL patients 19-42 months after receiving VEN. Other resistance mutations identified clinically so far include D103, A113G, R129L, and V156D, etc. Overcoming VEN-resistant Bcl-2 mutations represent an unmet medical need. Here, we introduce a novel and selective second-generation oral BCL-2 inhibitor, FCN-683, with sub-nano or single nanomolar affinity to BCL-2 and VEN-resistant BCL-2 mutations including G101V, D103E/V/Y, F104L, A113G, R129L and V156D. FCN-683 showed much higher affinity to BCL-2 than BCL-xL, suggesting its good potential to avoid BCL-xL-linked thrombocytopenia. FCN-683 exhibited comparable or superior anti-proliferation activities compared with VEN in various BCL-2-addicted human B-cell lymphoma cells, including DOHH2 follicular lymphoma cells, Toledo diffuse large B-cell lymphoma cells, and RS4;11 acute lymphoblastic leukemia cells, while sparing BCL-xL-dependent cells. Of note, FCN-683 displayed potent anti-proliferative activities against a panel of genetically engineered RS4;11 cells ectopically expressing VEN-resistant BCL-2 mutants such as G101V, D103 or several other mutants above-mentioned, outperforming VEN. Correspondingly, FCN-683 significantly inhibited tumor growth in mice xenografts derived from human B-cell lymphomas harboring BCL-2 or various VEN-resistant BCL-2 mutations and its anti-tumor efficacy was much superior to VEN. In non-clinical studies, FCN-683 possessed excellent pharmacokinetic (PK) properties comparable to VEN. Preferable safety profiles of FCN-683 were shown with no potential hERG inhibitory effect and less drug-drug interaction potential, as evidenced by no inhibitory effect (IC50 &gt;50 μM) on CYP2C9 enzyme compared with VEN (IC50 1.05 μM). Together, FCN-683 is highly potent, selective and highly efficacious against a variety of clinically relevant VEN-resistance BCL-2 mutations in vitro and in vivo and exhibits favorable PK and safety profiles, highlighting its therapeutic potential to become an effective therapeutic approach for VEN-naïve or -resistant BCL-2-addicted B-cell malignancies.
Citation Format: Shu (Sophie) Lin, Hongbin Liu, Rui Tan, Weipeng Zhang, Chengxi He, Yue Rong, Zhuo Huang, Jinhua Yu, Yunling Wang, Yangli Qi, Xingdong Zhao, Lihua Jiang, Yanxin Liu, Xilei Wang, Zongyao Zou, Jing Sun, Yuwei Gao, Weibo Wang, Xiaohui Guan, Yifang Wu. FCN-683, a novel second-generation BCL-2 inhibitor, is highly potent, selective and efficacious against clinically relevant venetoclax-resistant mutations [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 2531.