Journal
TRENDS IN PHARMACOLOGICAL SCIENCES
Volume 43, Issue 3, Pages 206-220Publisher
CELL PRESS
DOI: 10.1016/j.tips.2021.11.001
Keywords
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Categories
Funding
- Irma T. Hirschl Trust Career Award
- Pershing Square Sohn Cancer Research Alliance Award
- [R01CA178394]
- [PR191593P1]
- [P30CA013330]
- [P30AG038072]
- [P01AG031782]
- [F30CA228453]
- [T32GM007288]
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In this article, recent studies on the activation of BAX protein are discussed, providing structure-function insights and identifying regulatory surfaces that control BAX activation. The development of small molecule modulators is emphasized as a novel approach towards understanding and targeting BAX for therapeutic purposes.
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.
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