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Crystal Structures of PI3K? Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.

ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3K?-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3K?-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3K? inhibitors.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC4027628 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.

Zhao Yanlong Y Zhang Xi X Chen Yingyi Y Lu Shaoyong S Peng Yuefeng Y Wang Xiang X Guo Chengliang C Zhou Aiwu A Zhang Jingmiao J Luo Yu Y Shen QianCheng Q Ding Jian J Meng Linghua L Zhang Jian J

ACS medicinal chemistry letters 20131210 2

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via fo ...[more]

PMID: 24900786

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Crystal Structures of PI3K? Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.

Publications

Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.

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