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

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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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 - 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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