Proteomics

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HDX-MS of Activators and Inhibitors of PI3Kalpha


ABSTRACT: Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development. This also applies to the PI 3-kinase (PI3K) signalling pathway which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation1-3. Here we report on the discovery of UCL-TRO-1938 (further referred to as 1938), a small molecule activator of the PI3Kα isoform, a critical effector of growth factor signalling. 1938 allosterically activates PI3Kα through a unique mechanism, by enhancing multiple steps of the PI3Kα catalytic cycle, and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Ka over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia reperfusion injury and, upon local administration, enhances nerve regeneration following nerve crush. This study identifies a unique chemical tool to directly probe PI3Kα signalling and a novel approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes, through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

INSTRUMENT(S): SELECT SERIES Cyclic IMS

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Glenn Masson  

LAB HEAD: Glenn Masson

PROVIDER: PXD037721 | Pride | 2023-03-06

REPOSITORIES: Pride

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Publications

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Gong Grace Q GQ   Bilanges Benoit B   Allsop Ben B   Masson Glenn R GR   Roberton Victoria V   Askwith Trevor T   Oxenford Sally S   Madsen Ralitsa R RR   Conduit Sarah E SE   Bellini Dom D   Fitzek Martina M   Collier Matt M   Najam Osman O   He Zhenhe Z   Wahab Ben B   McLaughlin Stephen H SH   Chan A W Edith AWE   Feierberg Isabella I   Madin Andrew A   Morelli Daniele D   Bhamra Amandeep A   Vinciauskaite Vanesa V   Anderson Karen E KE   Surinova Silvia S   Pinotsis Nikos N   Lopez-Guadamillas Elena E   Wilcox Matthew M   Hooper Alice A   Patel Chandni C   Whitehead Maria A MA   Bunney Tom D TD   Stephens Len R LR   Hawkins Phillip T PT   Katan Matilda M   Yellon Derek M DM   Davidson Sean M SM   Smith David M DM   Phillips James B JB   Angell Richard R   Williams Roger L RL   Vanhaesebroeck Bart B  

Nature 20230524 7963


Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development<sup>1-5</sup>. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial eff  ...[more]

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