Development of a highly potent and selective degrader of LRRK2

John M. Hatcher, Monika Zwirek, Adil R. Sarhan, Prasanna S. Vatsan, Francesca Tonelli, Dario R. Alessi, Paul Davies, Nathanael S. Gray (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number129449
Number of pages7
JournalBioorganic & Medicinal Chemistry Letters
Volume94
Early online date15 Aug 2023
DOIs
Publication statusPublished - 1 Oct 2023

Keywords

  • LRRK2
  • LRRK2 degrader
  • MLi-2
  • PROTAC

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry

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