Abstract 792: A novel covalent reversible BTK inhibitor for B cell malignancies with enhanced selectivity and in vivo efficacy

Abstract

Bruton's tyrosine kinase (BTK), a member of Tec family kinase, plays a pivotal role in the regulation of BCR signaling, which is important for B cell development and function. Ibrutinib, which has been approved by FDA, is an effective treatment option for multiple types of B cell neoplasms. However, the treatment associated adverse events (AEs) are one of the major concerns due to its poor kinase selectivity . Here, we present a novel covalent, but reversible BTK inhibitor, XNW-1011, which demonstrated enhanced potency, better selectivity, improved drug-like properties and superior in vivo efficacy with a favorable safety profile. XNW-1011 was developed structurally and biochemically differently from current BTK inhibitors, being more potent and highly selective. In the in vitro assay, unlike Ibrutinib, it did not inhibit EGFR, ITK, JAK3, LYN and SRC. It completely suppressed the cell proliferation of a panel of lymphoma cell lines such as TMD-8 and Rec-1. Besides, XNW-1011 inhibited cellular phosphorylation of BTK and calcium efflux, confirming the inhibition of activation of BTK in vitro. We have shown that XNW-1011 formed covalent bond with cysteine in a cysteine reactivity assay. In addition, a washout assay by Western Blot confirmed the reversibility of inhibition of XNW-1011 to BTK. XNW-1011 has a good prolife of ADME, which translated into improved in vivo PK properties over Ibrutinib (low clearance and prolonged half-life). XNW-1011 was further evaluated in several animal models such as REC-1 and TMD-8 tumor xenografts. XNW-1011 inhibited tumor growth with as low as 3.125 mpk by BID and resulted in tumor regression with 12.5 mpk by BID. Interestingly, XNW-1011 completely inhibited the tumor growth of a patient derived xenograft (PDX) with Myd88 mutation. The dose proportionality was confirmed through determination of the plasma concentration and in vivo BTK occupancy in the last day of treatment. In summary, XNW-1011 is a potent, selective, covalent reversible BTK inhibitor with improved ADME prolife and in vivo efficacy, which makes it suitable for further evaluation in clinical setting. Citation Format: Xi Chen, Shaoqiang Huang, Fred Hu, Jun Xian, Jian Yang, Jing Qiang, Meijie Le, Yuchuan Wu. A novel covalent reversible BTK inhibitor for B cell malignancies with enhanced selectivity and in vivo efficacy [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 792.