B-cell lymphoma-2 (Bcl-2), an anti-apoptosis protein, is overexpressed and results in oncogenesis or drug resistance in various tumor types, including lymphoma and leukemia. Bcl-2 is a well-validated target for B cell malignancies as demonstrated by a selective Bcl-2 inhibitor venetoclax approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). However, in terms of other Bcl-2 mediated malignancies such as multiple myeloma (MM), the potency of venetoclax needs to be improved to achieve deep and durable clinical benefit. In addition, despite of the remarkably clinical activity in patients with CLL, recurrent multiple mutations including G101V in Bcl-2 has been reported to mediate resistance to venetoclax after longer term treatment. Therefore, it is desirable to design and discover new compounds which can present obviously increased potency for wild type Bcl-2 as well as efficacious inhibition on mutated Bcl-2. In this poster, a series of novel Bcl-2 inhibitors with unique fragment binding into P2 pocket will be presented. The comprehensive structure optimizations lead to clinical candidate BGB-11417. BGB-11417 potently inhibits Bcl-2 and Bcl-2-G101V proteins in biochemical assays, with IC<sub>50</sub> of 0.014 nM and 0.59 nM, respectively. BGB-11417 is also highly selective for Bcl-2, showing ≥2000 folds selectivity to Bcl-xL, Bcl-w, Mcl-1 and Bcl2A1. Furthermore, BGB-11417 demonstrates significantly greater efficacy than venetoclax in various xenograft mouse models, such as human acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and DLBCL (diffuse large B-cell lymphoma).<br/>Collectively, BGB-11417 is a highly potent and selective Bcl-2 inhibitor with superior in vitro potency and anti-tumor activities compared with venetoclax in preclinical studies. Our efforts may provide the opportunity to develop a novel Bcl-2 inhibitor which presents more benefits in CLL patients as well as other Bcl-2 mediated malignancies. BGB-11417 is currently undergoing phase1/2 clinical assessment in monotherapy or combination.

Novel Bcl-2 inhibitor BGB-11417 with excellent potency for both wild type Bcl-2 and G101V-mutated Bcl-2

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.