The Chemical Diversity and Structure-based Discovery of Allosteric Modulators for the PIF-pocket of Protein Kinase PDK1

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2019 Feb 9

PMID 30734603

Citations 9

Authors

Xinyuan Xu

Yingyi Chen

Qiang Fu

Duan Ni

Jian Zhang

Xiaolong Li

Shaoyong Lu

Affiliations

Soon will be listed here.

Abstract

Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.

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