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The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

Vogler, Meike, Braun, Yannick, Smith, Victoria M., Westhoff, Mike-Andrew, Pereira, Raquel S., Pieper, Nadja M., Anders, Marius, Callens, Manon, Vervliet, Tim, Abbas, Maha, Macip, Salvador, Schmid, Ralf, Bultynck, Geert, Dyer, Martin JS·2025·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-025-02176-0PMC PMC11926181
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Abstract

The B cell lymphoma 2 (BCL2) protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-X L and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-X L or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-X L and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-X L or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.

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  • PROTACs are bifunctional molecules that simultaneously bind a target protein and an E3 ubiquitin ligase, promoting ubiquitination and proteasomal degradation of the target.

    “These bifunctional molecules function as molecular matchmakers, simultaneously binding a target protein (e.g., BCL-xL) and an E3 ubiquitin ligase80. This induced proximity promotes ubiquitination of the target protein, directing it to the proteasome for complete degradation81–83.”

    From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [80]

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Metadata

Authors
Vogler, M., Braun, Y., Smith, V. M., Westhoff, M.-A., Pereira, R. S., Pieper, N. M., Anders, M., Callens, M., Vervliet, T., Abbas, M., Macip, S., Schmid, R., Bultynck, G., & Dyer, M. J.
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2025-03-21
Volume
10
Issue
1
ISSN
2059-3635
DOI
10.1038/s41392-025-02176-0
PMC
PMC11926181
Cited by
462
References
40
Language
en
Licence
Funders
  • Deutsche Krebshilfe (70114124)
  • Deutsche Kinderkrebsstiftung (DKS A2023_01)
  • Goethe-Universität Frankfurt am Main (Junior Clinical Scientist programme)
  • Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (PI20/00328)
  • Fonds Wetenschappelijk Onderzoek (G0E7520N, G081821N and G094522N)
  • Scott-Waudby Trust, Hope Against Cancer Charity

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