Format

Send to

Choose Destination
Bioorg Med Chem. 2017 Feb 15;25(4):1481-1486. doi: 10.1016/j.bmc.2017.01.012. Epub 2017 Jan 16.

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

Author information

1
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
2
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
3
Schrödinger, Inc., 120 West 45th Street, New York, NY 10036, United States.
4
Ludwig Center and Howard Hughes Medical Institutions, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
5
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.

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.

KEYWORDS:

Fragment-based drug discovery; PI3K; PIK3CA; PIP(2); PIP(3)

PMID:
28129991
PMCID:
PMC5319926
DOI:
10.1016/j.bmc.2017.01.012
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center