Development of a highly potent and selective degrader of LRRK2.

Animals Models, Animal Mutation Parkinson Disease / drug therapy Phosphorylation Proteolysis Targeting Chimera Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors
LRRK2 LRRK2 degrader MLi-2 PROTAC

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
01 10 2023
Historique:
received: 12 04 2023
revised: 06 07 2023
accepted: 14 08 2023
medline: 18 9 2023
pubmed: 18 8 2023
entrez: 17 8 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.bmcl.2023.129449 PMID: 37591317
pubmed: 37591317
pii: S0960-894X(23)00327-X
doi: 10.1016/j.bmcl.2023.129449
pii:
doi:

Substances chimiques

Proteolysis Targeting Chimera 0
LRRK2 protein, human EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

129449

Subventions

Organisme : Medical Research Council
ID : MC_UU_00018/1
Pays : United Kingdom

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

John M Hatcher (JM)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.

Monika Zwirek (M)

MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.

Adil R Sarhan (AR)

Department of Medical Laboratory Techniques, Nasiriyah Technical Institute, Southern Technical University, Nasiriyah 64001, Iraq.

Prasanna S Vatsan (PS)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.

Francesca Tonelli (F)

MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.

Dario R Alessi (DR)

MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.

Paul Davies (P)

MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.

Nathanael S Gray (NS)

Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: nsgray01@stanford.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Development of a highly potent and selective...
questionsmedicales.fr › Techniques d'investigation › Modèles animaux › Development of a highly potent and selective...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Development of a highly potent and selective...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Development of a highly potent and selective...
questionsmedicales.fr › Métabolisme › Phosphorylation › Development of a highly potent and selective...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Indicateurs et réactifs › Réactifs réticulants › Chimère ciblant la protéolyse › Development of a highly potent and selective...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Leucine-rich repeat serine-threonine protein kinase-2 › Development of a highly potent and selective...