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@ARTICLE{Vogler:300099,
author = {M. Vogler$^*$ and Y. Braun and V. M. Smith and M.-A.
Westhoff and R. S. Pereira and N. M. Pieper and M. Anders
and M. Callens and T. Vervliet and M. Abbas and S. Macip and
R. Schmid and G. Bultynck and M. J. Dyer},
title = {{T}he {BCL}2 family: from apoptosis mechanisms to new
advances in targeted therapy.},
journal = {Signal transduction and targeted therapy},
volume = {10},
number = {1},
issn = {2095-9907},
address = {London},
publisher = {Macmillan Publishers, part of Springer Nature},
reportid = {DKFZ-2025-00599},
pages = {91},
year = {2025},
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-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.},
subtyp = {Review Article},
keywords = {Humans / Proto-Oncogene Proteins c-bcl-2: antagonists $\&$
inhibitors / Proto-Oncogene Proteins c-bcl-2: genetics /
Apoptosis: drug effects / Apoptosis: genetics / Neoplasms:
drug therapy / Neoplasms: genetics / Neoplasms: pathology /
Neoplasms: metabolism / Molecular Targeted Therapy /
Sulfonamides: therapeutic use / Sulfonamides: pharmacology /
Myeloid Cell Leukemia Sequence 1 Protein: genetics / Myeloid
Cell Leukemia Sequence 1 Protein: antagonists $\&$
inhibitors / Myeloid Cell Leukemia Sequence 1 Protein:
metabolism / Bridged Bicyclo Compounds, Heterocyclic:
therapeutic use / bcl-X Protein: genetics / bcl-X Protein:
antagonists $\&$ inhibitors / Proto-Oncogene Proteins
c-bcl-2 (NLM Chemicals) / BCL2 protein, human (NLM
Chemicals) / Sulfonamides (NLM Chemicals) / venetoclax (NLM
Chemicals) / Myeloid Cell Leukemia Sequence 1 Protein (NLM
Chemicals) / Bridged Bicyclo Compounds, Heterocyclic (NLM
Chemicals) / MCL1 protein, human (NLM Chemicals) / bcl-X
Protein (NLM Chemicals)},
cin = {FM01},
ddc = {610},
cid = {I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40113751},
pmc = {pmc:PMC11926181},
doi = {10.1038/s41392-025-02176-0},
url = {https://inrepo02.dkfz.de/record/300099},
}