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

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• 作者：Michelle S. Miller^a ; Sweta Maheshwari^b ; Fiona M. McRobb^c ; Kenneth W. Kinzler^d ; L. Mario Amzel^b ; Bert Vogelstein^d ; Sandra B. Gabelli^a ; ^b ; ^e ; ^{gabelli@jhmi.edu}
• 关键词：PIK3CA ; PI3K ; PIP2 ; PIP3 ; Fragment-based drug discovery
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：25
• 期：4
• 页码：1481-1486
• 全文大小：1511 K
• 卷排序：25

文摘

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.