title: Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design.
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<300Da) 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.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Miller
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
authors.forename: Sweta
authors.initials: S
authors.lastname: Maheshwari
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, New York, NY 10036, United States.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: McRobb
authors.affiliation: Ludwig Center and Howard Hughes Medical Institutions, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
authors.affiliation: Ludwig Center and Howard Hughes Medical Institutions, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States. Electronic address: gabelli@jhmi.edu.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Gabelli
mesh_terms: D000495:Allosteric Site / Q000187:drug effects / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C484760:PIK3CA protein, human
keywords: Fragment-based drug discovery; PI3K; PIK3CA; PIP(2); PIP(3)