Type-II Kinase Inhibitors That Target Parkinson's Disease-associated LRRK2

Overview

Journal bioRxiv

Date 2024 Nov 18

PMID 39554022

Authors

Nicolai D Raig

Katherine J Surridge

Marta Sanz-Murillo

Verena Dederer

Andreas Kramer

Martin P Schwalm

Lewis Elson

Deep Chatterjee

Sebastian Mathea

Thomas Hanke

Andres E Leschziner

Samara L Reck-Peterson

Stefan Knapp

Affiliations

Soon will be listed here.

Abstract

Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD). Numerous LRRK2-selective type-I kinase inhibitors have been developed and some have entered clinical trials. In this study, we present the first LRRK2-selective type-II kinase inhibitors. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type-I inhibitors. We designed these inhibitors using a combinatorial chemistry approach fusing selective LRRK2 type-I and promiscuous type-II inhibitors by iterative cycles of synthesis supported by structural biology and activity testing. Our current lead structures are selective and potent LRRK2 inhibitors. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation, and expand the potential therapeutic options for PD.

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