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

Michelle S. Miller, Sweta Maheshwari, Fiona M. McRobb, Kenneth W Kinzler, Mario L Amzel, Bert Vogelstein, Sandra B Gabelli

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)1481-1486
Number of pages6
JournalBioorganic and Medicinal Chemistry
Issue number4
StatePublished - Feb 15 2017



  • Fragment-based drug discovery
  • PI3K
  • PIK3CA
  • PIP
  • PIP

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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