Targeting BAX to drug death directly.

Abstract:

:BCL-2 family protein interactions regulate apoptosis, a critical process that maintains tissue homeostasis but can cause a host of human diseases when deregulated. Venetoclax is the first FDA-approved drug to reactivate apoptosis in cancer by selectively targeting an anti-apoptotic BCL-2 family member. The drug's activity relies on an 'inhibit the inhibitor' mechanism, whereby blockade of a key surface groove on BCL-2 disables its capacity to neutralize pro-apoptotic effectors, such as BAX, a chief executioner protein of the apoptotic pathway. A series of physiologic and pharmacologic regulatory sites that mediate the activation or inhibition of BAX have recently been identified, providing blueprints for the development of alternative apoptosis modulators to block pathologic cell survival or avert unwanted cell death by drugging BAX directly.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Walensky LD

doi

10.1038/s41589-019-0306-6

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

657-665

issue

7

eissn

1552-4450

issn

1552-4469

pii

10.1038/s41589-019-0306-6

journal_volume

15

pub_type

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