Mode of action
The B-cell lymphoma 2 (BCL2) gene family encodes more than 20 proteins that regulate the intrinsic apoptosis pathway, and are fundamental to the balance between cell survival and cell death.2
Acquiring resistance to apoptosis is a highly regulated process, characteristic of both hematologic malignancies and solid tumors.2,3 Anti-apoptotic BCL2 has been shown to promote malignant cell survival by attenuating apoptosis. The dysregulation of BCL2 results in overexpression of the anti-apoptotic protein BCL2 which alters the balance of pro-apoptotic members of the BCL2 family. In normal cells, cell death signals trigger BID and BIM to activate BAX and BAK. Oligomerization of the pro-apoptotic proteins BAX and BAK, results in mitochondrial outer membrane permeabilization (MOMP), the release of cytochrome c and second mitochondria-derived activator of caspase (SMAC) from the mitochondria and the subsequent activation of caspases resulting in cell death.2
Anti-apoptotic BCL2 sequesters pro-apoptotic proteins such as BAX and BAK by binding to their BH3 motifs leading to inhibitions of the intrinsic apoptosis pathway.2
BGB-11417 acts as a BH3 mimetic. By binding to BCL2, it induces BAX-BAK-dependent apoptosis. BCL2 is a well-validated target for B-cell malignancies. With long term treatment, recurrent mutation of G10V in BCL2 has been reported to mediate resistance to BCL2 inhibitors. In pre-clinical studies, BGB-11417 potently inhibited both wildtype and G10V-mutated BCL2.1
BGB-11417 in clinical trials
BGB-11417 is currently being investigated in a phase 1a/1b trial in patients with non-Hodgkin lymphomas (NHLs) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with either BGB-11417 monotherapy or in combination with zanubrutinib.
For an exhaustive list of BGB-11417 monotherapy and combination clinical trials, view the development program.
- Hu, N. et al. Abstract 3077: Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in haematological tumor models. Cancer Res 2020;80:3077.
- Ashkenazi, A., Fairbrother, W. J., Leverson, J. D. & Souers, A. J. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat. Rev. Drug Discov 2017;16: 273–284.
- Montero, J. & Letai, A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ 2018;25:56–64.