From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors

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Updated: Mar 7, 2026

Examining BCL-2 Family Function with Large Unilamellar Vesicles
08:35

Examining BCL-2 Family Function with Large Unilamellar Vesicles

Published on: October 5, 2012

8.4K

Avi Ashkenazi1, Wayne J Fairbrother1, Joel D Leverson2

  • 1Genentech, 1 DNA Way, South San Francisco, California 94080, USA.

Nature Reviews. Drug Discovery
|February 18, 2017
PubMed

Insights

Targeting B-cell lymphoma 2 (BCL-2) family proteins offers a promising cancer therapy strategy. Selective inhibitors, like venetoclax, are advancing treatment for certain leukemias by restoring programmed cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The B-cell lymphoma 2 (BCL-2) gene family regulates programmed cell death (apoptosis).
  • Dysregulation of BCL-2 family genes, particularly anti-apoptotic members, is a hallmark of cancer, enabling tumor cells to evade apoptosis.
  • Targeting these anti-apoptotic proteins presents a significant therapeutic opportunity in oncology.

Purpose of the Study:

  • To review recent advancements in the direct and selective targeting of BCL-2 family proteins for cancer therapy.
  • To highlight the development and clinical progress of BCL-2 family inhibitors.

Main Methods:

  • Utilized nuclear magnetic resonance (NMR)-based screening and structure-based drug design to identify BCL-2 homology 3 (BH3) mimetics.
  • Reviewed clinical data and development pathways for BCL-2 family inhibitors.

Main Results:

  • Navitoclax, a dual BCL-2 and BCL-XL antagonist, was the first BCL-2 family inhibitor demonstrating clinical efficacy in cancer patients.
  • Venetoclax, a selective BCL-2 inhibitor, is approved for treating chronic lymphocytic leukemia with 17p deletion.
  • Development of potent and selective inhibitors for BCL-XL and myeloid cell leukemia 1 (MCL1) is progressing.

Conclusions:

  • Direct and selective inhibition of BCL-2 family proteins is a validated and evolving strategy in cancer treatment.
  • Ongoing research focuses on developing novel inhibitors targeting key anti-apoptotic members like BCL-2, BCL-XL, and MCL1.

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