Sonrotoclax

Sonrotoclax is a potent and selective inhibitor of BCL2.1

24 Jan 2025

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

Sonrotoclax 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, sonrotoclax potently inhibited both wildtype and G10V-mutated BCL2.1

BGB-11417_Compound_V2

Sonrotoclax in clinical trials

Sonrotoclax 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 sonrotoclax monotherapy or in combination with zanubrutinib.

For an exhaustive list of sonrotoclax monotherapy and combination clinical trials, view the development program.

Sonrotoclax is not authorized for use in the EU.

References

  1. 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.
  2. 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.
  3. 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.