Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl‑2

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2)
selective
inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated
that the antiapoptotic protein Bcl-2 is a druggable target for B-cell
malignancies. However, venetoclax’s limited potency cannot
produce a strong, durable clinical benefit in other Bcl-2-mediated
malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent
Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance
to venetoclax after long-term treatment. Herein, we described novel
Bcl-2 inhibitors with increased potency for both wild-type (WT) and
mutant Bcl-2. Comprehensive structure optimization led to the clinical
candidate BGB-11417 (compound 12e, sonrotoclax), which
exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant,
as well as excellent selectivity over Bcl-xL without obvious
cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase
II/III clinical assessments as monotherapy and combination treatment.