Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design. Issue 4 (15th February 2017)

• Record Type: Journal Article
• Authors: Miller, Michelle S.; Maheshwari, Sweta; McRobb, Fiona M.; Kinzler, Kenneth W.; Amzel, L. Mario; Vogelstein, Bert; Gabelli, Sandra B.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 4(2017)
• Page Start: 1481
• Page End: 1486
• Publication Date: 2017-02-15
• Subjects: PIK3CA -- PI3K -- PIP2 -- PIP3 -- Fragment-based drug discovery; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.01.012
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW < 300 Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.