A GCN1-independent activator of the kinase GCN2

TY - UNPB

T1 - A GCN1-independent activator of the kinase GCN2

AU - Zhu, JiaYi

AU - Emanuelli, Giulia

AU - Masson, Glenn

AU - Vinciauskaite, Vanesa

AU - Willems, Henriette

AU - Lim, Andrew

AU - Brown, Christopher Alan

AU - Winpenny, David

AU - Clarke, Murray

AU - Gilley, Rebecca

AU - Preston, Fergus

AU - Wilson, Jordan

AU - Bader, Aldo

AU - Rahman, Taufiq

AU - Chambers, Joseph E

AU - Skidmore, John

AU - Morrell, Nicholas W

AU - Marciniak, Stefan J

PY - 2025/7/3

Y1 - 2025/7/3

N2 - Mutations of EIF2AK4, which encodes the eIF2α kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP-pocket binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP-pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.

AB - Mutations of EIF2AK4, which encodes the eIF2α kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP-pocket binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP-pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.

U2 - 10.1101/2025.06.29.662197

DO - 10.1101/2025.06.29.662197

M3 - Preprint

BT - A GCN1-independent activator of the kinase GCN2

PB - BioRxiv

ER -