Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• The gene PIK3CA encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα).
• Mutations in PIK3CA are common in various cancers, including breast cancer.
• Targeting mutant PI3Kα could enhance treatment efficacy and reduce side effects.

Purpose of the Study:

• To identify novel binding pockets in PI3Kα for the design of mutant-selective inhibitors.
• To explore opportunities for developing targeted cancer therapies.

Main Methods:

• Utilized a fragment-based screening approach.
• Screened 352 small molecule fragments (molecular weight < 300 Da).
• Employed X-ray crystallography to analyze fragment binding to PI3Kα.

Main Results:

• Identified five novel binding pockets within PI3Kα.
• Discovered a promising binding pocket near the frequently mutated Glu542 residue.
• These pockets offer potential sites for designing selective PI3Kα inhibitors.

Conclusions:

• The identified binding pockets represent new avenues for developing mutant-selective PI3Kα inhibitors.
• This research could facilitate the design of more effective and safer cancer treatments.