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

doi:10.1016/j.bmcl.2023.129449

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)

MRC PPU

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

31 Downloads (Pure)

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 language	English
Article number	129449
Number of pages	7
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	94
Early online date	15 Aug 2023
DOIs	https://doi.org/10.1016/j.bmcl.2023.129449
Publication status	Published - 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

Access to Document

10.1016/j.bmcl.2023.129449Licence: Elsevier User Licence

Author Accepted ManuscriptAccepted author manuscript, 1.38 MBLicence: CC BY-NC-ND

Cite this

@article{20fc0f2bb51b42c4b799add7d51d99d9,

title = "Development of a highly potent and selective degrader of LRRK2",

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.",

keywords = "LRRK2, LRRK2 degrader, MLi-2, PROTAC",

author = "Hatcher, {John M.} and Monika Zwirek and Sarhan, {Adil R.} and Vatsan, {Prasanna S.} and Francesca Tonelli and Alessi, {Dario R.} and Paul Davies and Gray, {Nathanael S.}",

note = "Funding Information: N.G and D.R.A acknowledge The Michael J Fox Foundation (Grant MJFF-005430), D.R.A is supported by the UK Medical Research Council [grant number MC_UU_00018/1]. D.R.A and P.D are also supported by and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer Ingelheim, GlaxoSmithKline, Merck KGaA.). Copyright: {\textcopyright} 2023. Published by Elsevier Ltd.",

year = "2023",

month = oct,

day = "1",

doi = "10.1016/j.bmcl.2023.129449",

language = "English",

volume = "94",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier",

}

TY - JOUR

T1 - Development of a highly potent and selective degrader of LRRK2

AU - Hatcher, John M.

AU - Zwirek, Monika

AU - Sarhan, Adil R.

AU - Vatsan, Prasanna S.

AU - Tonelli, Francesca

AU - Alessi, Dario R.

AU - Davies, Paul

AU - Gray, Nathanael S.

N1 - Funding Information: N.G and D.R.A acknowledge The Michael J Fox Foundation (Grant MJFF-005430), D.R.A is supported by the UK Medical Research Council [grant number MC_UU_00018/1]. D.R.A and P.D are also supported by and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer Ingelheim, GlaxoSmithKline, Merck KGaA.). Copyright: © 2023. Published by Elsevier Ltd.

PY - 2023/10/1

Y1 - 2023/10/1

N2 - 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.

AB - 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.

KW - LRRK2

KW - LRRK2 degrader

KW - MLi-2

KW - PROTAC

U2 - 10.1016/j.bmcl.2023.129449

DO - 10.1016/j.bmcl.2023.129449

M3 - Article

C2 - 37591317

SN - 0960-894X

VL - 94

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

M1 - 129449

ER -

Development of a highly potent and selective degrader of LRRK2

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this