1. Development of a highly potent and selective degrader of LRRK2.
- Author
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Hatcher JM, Zwirek M, Sarhan AR, Vatsan PS, Tonelli F, Alessi DR, Davies P, and Gray NS
- Subjects
- Animals, Models, Animal, Mutation, Phosphorylation, Proteolysis Targeting Chimera, Parkinson Disease drug therapy, Parkinson Disease genetics, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors
- Abstract
The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. Furthermore, LRRK2 function as a scaffolding protein in several pathways has been implicated as a plausible mechanism underlying neurodegeneration caused by LRRK2 mutations. Given that both the kinase activity and scaffolding function of LRRK2 have been linked to neurodegeneration, we developed proteolysis-targeting chimeras (PROTACs) targeting LRRK2. The degrader molecule JH-XII-03-02 (6) displayed high potency and remarkable selectivity for LRKK2 when assessed in a of 468 panel kinases and serves the dual purpose of eliminating both the kinase activity as well as the scaffolding function of LRRK2., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nathanael Gray is a founder, science advisory board member (SAB) and equity holder in Gatekeeper, Syros, Petra, C4, B2S, Aduro, Inception, Allorion, Jengu and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield and Sanofi. John Hatcher is a scientific advisor to Arbella Therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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