Physiological and pharmacological modulation of BAX

Adam Z. Spitz; Evripidis Gavathiotis

doi:10.1016/j.tips.2021.11.001

Physiological and pharmacological modulation of BAX

Adam Z. Spitz, Evripidis Gavathiotis

Biochemistry

Research output: Contribution to journal › Review article › peer-review

87 Scopus citations

Abstract

Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure–function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX.

Original language	English (US)
Pages (from-to)	206-220
Number of pages	15
Journal	Trends in Pharmacological Sciences
Volume	43
Issue number	3
DOIs	https://doi.org/10.1016/j.tips.2021.11.001
State	Published - Mar 2022

Keywords

BAX
BAX activators
BAX inhibitors
BCL-2 family
apoptosis
mitochondria

ASJC Scopus subject areas

Toxicology
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.tips.2021.11.001

Cite this

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title = "Physiological and pharmacological modulation of BAX",

abstract = "Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure–function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX.",

keywords = "BAX, BAX activators, BAX inhibitors, BCL-2 family, apoptosis, mitochondria",

author = "Spitz, {Adam Z.} and Evripidis Gavathiotis",

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year = "2022",

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doi = "10.1016/j.tips.2021.11.001",

language = "English (US)",

volume = "43",

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AU - Spitz, Adam Z.

AU - Gavathiotis, Evripidis

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N2 - Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure–function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX.

AB - Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure–function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX.

KW - BAX

KW - BAX activators

KW - BAX inhibitors

KW - BCL-2 family

KW - apoptosis

KW - mitochondria

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DO - 10.1016/j.tips.2021.11.001

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JO - Trends in Pharmacological Sciences

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Physiological and pharmacological modulation of BAX

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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