BH3 Mimetics for the Treatment of B-Cell Malignancies-Insights and Lessons from the Clinic

Cancers
Victor S LinRachel Thijssen

Abstract

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid ce...Continue Reading

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Citations

Apr 28, 2021·Nanomedicine·Neha MehrotraHarpal Singh
Jun 3, 2021·Cancers·Marta Cuenca, Victor Peperzak
Sep 28, 2021·Frontiers in Cell and Developmental Biology·Albert Manzano-MuñozJoan Montero

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Methods Mentioned

BETA
nuclear magnetic resonance
xenograft
biopsy
NMR
xenografts

Clinical Trials Mentioned

NCT01328626
NCT01889186
NCT02141282
NCT01682616
NCT02005471
NCT02242942
NCT02427451
NCT02401503
NCT03112174
NCT02055820

Software Mentioned

VenKd
ENDEAVOR

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