Structural insights into the interaction of three Y-shaped ligands with PI3Kα

Author:

Zhou Qingtong1ORCID,Liu Xiao1,Neri Dario2,Li Wenxin1,Favalli Nicholas2,Bassi Gabriele2,Yang Su3,Yang Dehua4ORCID,Vogt Peter K.3ORCID,Wang Ming-Wei1567ORCID

Affiliation:

1. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

2. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich 8093, Switzerland

3. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037

4. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

5. Research Center for Deepsea Bioresources, Sanya 572025, China

6. Department of Chemistry, School of Science, The University of Tokyo, Tokyo 113-0033, Japan

7. School of Pharmacy, Hainan Medical College, Haikou 570228, China

Abstract

Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα.

Funder

MOST | National Natural Science Foundation of China

National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program

STI2030-Major Project

National Key Basic Research Program of China

Hainan Provincial Major Science and Technology Project

Novo Nordisk-Chinese Academy of Sciences Research Fund

HHS | NIH | National Cancer Institute

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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