Abstract 5438: FCN-589, a novel, potent and selective BTK inhibitor, targets BTK C481S for the treatment of B-cell malignancies
Authors: Lin Shu , Tan Haohan , Liu Qihong , Wang Yunling , Liu Bin , Li Zhifu , Chen Zhifang , Wang Xianlong , Zhao Xingdong , Jiang Lihua , Wang Xilei , Cheng Tao , Zhou Jiashu , Wang Weibo 
Published: June 2022

Abstract
Bruton’s tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases and plays critical roles in B-cell receptor (BCR) signaling. BTK is often overexpressed in B-cells of patients with hematological malignancies. BTK inhibition blocks BCR signals, prevents B-cell activation and malignant B-cell growth, and induces apoptosis. Early irreversible BTK inhibitors such as ibrutinib, which covalently binds to the cysteine residue (C481) of BTK, are effective against B-cell malignancies and have received approval for various B-cell lymphomas and leukemia including mantle cell lymphoma and chronic lymphocytic leukemia, but their effectiveness is often limited by toxicities from off-target inhibition of the Tec (e.g., ITK/TEC) and EGFR family (e.g., EGFR/HER2/HER4). Acquired resistance mutations in the C481 binding site are known to cause clinical resistance to irreversible BTK inhibitors, which accounts for over half of progression in patients received ibrutinib. There is thus unmet medical need for a novel BTK inhibitor with improved safety profile efficacious against C481 mutation. Here we introduce FCN-589, a novel and orally active next-generation BTK inhibitor. FCN-589 shows potent kinase activities against wild-type (WT) BTK and the most common resistant mutation BTK C481S with single-digit nanomolar IC50 and improved selectivity over clinically significant off-targets such as TRK and ITK compared with nemtabrutinib (MK-1026, ARQ 531), another BTK C481S inhibitor in development. FCN-589 exhibits remarkable anti-proliferating potency against a panel of human B-cell malignancies-derived cancer cell lines. FCN-589 is over 30x more potent against follicular lymphoma cells (DOHH2) and activated B-cell subset of diffuse large B-cell lymphoma (DLBCL) cells (OCI-LY10 and Ri-1), and about 4x more potent against germinal center B-cell like subset of DLBCL cells (SU-DHL-4) compared with ARQ 531. In HEK-293 cell line ectopically expressing WT or BTK C481S, FCN-589 markedly inhibits p-BTK expression with superior activity compared with ARQ 531. Consistently, FCN-589 shows significant and superior anti-tumor activities in mice xenograft models derived from human non-Hodgkin’s lymphomas compared with ARQ 531 and ibrutinib. In non-clinical studies, FCN-589 exhibits good pharmacokinetic (PK) and safety properties. In particular, FCN-589 has longer T1/2 in both rats and dogs, displays improved CYP450 inhibition profile, and is less plasma protein bound compared with ARQ 531. Overall, FCN-589 is a novel next-generation BTK inhibitor targeting WT and BTK C481S. FCN-589 possesses potent in vitro and in vivo anti-cancer activities with better selectivity against clinically significant off-targets and exhibits favorable PK and safety profiles compared with ARQ 531. FCN-589 has potential to be a more effective and safer option for patients with B-cell malignancies.
Citation Format: Shu Lin, Haohan Tan, Qihong Liu, Yunling Wang, Bin Liu, Zhifu Li, Zhifang Chen, Xianlong Wang, Xingdong Zhao, Lihua Jiang, Xilei Wang, Tao Cheng, Jiashu Zhou, Weibo Wang. FCN-589, a novel, potent and selective BTK inhibitor, targets BTK C481S for the treatment of B-cell malignancies [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 5438.