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Examining BCL-2 Family Function with Large Unilamellar Vesicles
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Small molecule SJ572946 activates BAK to initiate apoptosis

Giridhar Sekar1,2, Geetika Singh1,2,3, Xingping Qin4,5,6

  • 1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Iscience
|September 23, 2022
PubMed

Insights

Researchers discovered SJ572946, a small molecule that directly activates BAK, a key protein in apoptosis. This molecule shows potential for cancer treatment by selectively inducing cell death in cancer cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Apoptosis, or programmed cell death, is initiated by the outer mitochondrial membrane permeabilization.
  • This process is mediated by BCL-2 family proteins, specifically the effector proteins BAK and BAX.
  • BH3-only proteins like BID and BIM activate BAK and BAX, leading to the formation of apoptotic pores.

Purpose of the Study:

  • To identify and characterize small molecules that can directly activate effector BCL-2 proteins for cancer therapy.
  • To investigate the mechanism of action and cellular activity of a novel small molecule, SJ572946.

Main Methods:

  • Fragment-based screening to discover SJ572946.
  • Liposome and mitochondrial permeabilization assays to assess protein activation.
  • Cell-based assays using BAK-expressing cancer cells (BCL2allKO HCT116) and experimental cancer cell lines.

Main Results:

  • SJ572946 selectively binds to and activates BAK, but not BAX.
  • The molecule induces BAK-dependent cell death in cancer cells.
  • SJ572946 enhances the efficacy of existing apoptosis inducers and BH3 mimetics.
  • It also cooperates with BID to activate a resistant BAK mutant.

Conclusions:

  • SJ572946 is a novel small molecule activator of BAK.
  • It demonstrates on-target cellular activity and potential for combination cancer therapy.
  • This molecule serves as a valuable tool for studying BAK-mediated apoptosis in preclinical research.
Keywords:
BiochemistryCell biologySmall moleculeStructural biology

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