TY  - JOUR
AU  - Vogler, Meike
AU  - Braun, Yannick
AU  - Smith, Victoria M
AU  - Westhoff, Mike-Andrew
AU  - Pereira, Raquel S
AU  - Pieper, Nadja M
AU  - Anders, Marius
AU  - Callens, Manon
AU  - Vervliet, Tim
AU  - Abbas, Maha
AU  - Macip, Salvador
AU  - Schmid, Ralf
AU  - Bultynck, Geert
AU  - Dyer, Martin Js
TI  - The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy.
JO  - Signal transduction and targeted therapy
VL  - 10
IS  - 1
SN  - 2095-9907
CY  - London
PB  - Macmillan Publishers, part of Springer Nature
M1  - DKFZ-2025-00599
SP  - 91
PY  - 2025
AB  - 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-XL and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-XL or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-XL and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-XL 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.
KW  - Humans
KW  - Proto-Oncogene Proteins c-bcl-2: antagonists & inhibitors
KW  - Proto-Oncogene Proteins c-bcl-2: genetics
KW  - Apoptosis: drug effects
KW  - Apoptosis: genetics
KW  - Neoplasms: drug therapy
KW  - Neoplasms: genetics
KW  - Neoplasms: pathology
KW  - Neoplasms: metabolism
KW  - Molecular Targeted Therapy
KW  - Sulfonamides: therapeutic use
KW  - Sulfonamides: pharmacology
KW  - Myeloid Cell Leukemia Sequence 1 Protein: genetics
KW  - Myeloid Cell Leukemia Sequence 1 Protein: antagonists & inhibitors
KW  - Myeloid Cell Leukemia Sequence 1 Protein: metabolism
KW  - Bridged Bicyclo Compounds, Heterocyclic: therapeutic use
KW  - bcl-X Protein: genetics
KW  - bcl-X Protein: antagonists & inhibitors
KW  - Proto-Oncogene Proteins c-bcl-2 (NLM Chemicals)
KW  - BCL2 protein, human (NLM Chemicals)
KW  - Sulfonamides (NLM Chemicals)
KW  - venetoclax (NLM Chemicals)
KW  - Myeloid Cell Leukemia Sequence 1 Protein (NLM Chemicals)
KW  - Bridged Bicyclo Compounds, Heterocyclic (NLM Chemicals)
KW  - MCL1 protein, human (NLM Chemicals)
KW  - bcl-X Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40113751
C2  - pmc:PMC11926181
DO  - DOI:10.1038/s41392-025-02176-0
UR  - https://inrepo02.dkfz.de/record/300099
ER  -