Leucine-rich repeat kinase 2 (LRRK2) inhibitors for Parkinson’s disease: a patent review of the literature to date

ABSTRACT

Introduction

Nearly two decades after leucine rich repeat kinase 2 (LRRK2) was discovered as a genetic determinant of Parkinson’s disease (PD), LRRK2 has emerged a priority therapeutic target in PD and inhibition of its activity is hypothesized to be beneficial.

Areas covered

LRRK2 targeting agents, in particular kinase inhibitors and agents reducing LRRK2 expression show promise in model systems and have progressed to phase I and phase II clinical testing for PD. Several additional targeting strategies for LRRK2 are emerging, based on promoting specific ‘healthy’ LRRK2 quaternary structures, heteromeric complexes and conformations.

Expert opinion

It can be expected that LRRK2 targeting strategies may proceed to phase III clinical testing for PD in the next five years, allowing the field to discover the real clinical value of LRRK2 targeting strategies.

KEYWORDS:

• LRRK2
• kinase
• allosteric
• GTPase
• Parkinson’s disease
• conformation

Article highlights

• LRRK2 is a priority therapeutic target in Parkinson’s disease and inhibition of its activity is hypothesized to be beneficial

• LRRK2 targeting agents, in particular kinase inhibitors and agents reducing LRRK2 expression show promise in model systems and have progressed to phase I and phase II clinical testing

• Several additional targeting strategies for LRRK2 are emerging, based on promoting specific ‘healthy’ LRRK2 quaternary structures, heteromeric complexes, and conformations

• It can be expected that LRRK2 targeting strategies may proceed to phase III clinical testing in the next five years, allowing the field to discover the real clinical value of LRRK2 targeting strategies

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors gratefully acknowledge financial support from the Michael J. Fox Foundation (grants MJFF 022431 and MJFF 023427) as well as from the Agence Nationale de la Recherche (grants ANR-21-CE16-0003-01 and ANR-23-CE44-0010).

Author contribution statement

All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature. MM, AJLO, and JMT wrote the article, JMT, MM, AJLO prepared Figures 1–3, NL prepared Figures 4–9, MM compiled the table overview of patents for LRRK2 targeting agents. All authors revised the review article for intellectual content.

Additional information

Funding

This paper was funded by the Agence Nationale de la Recherche [ANR-21-CE16-0003-01, ANR-23-CE44-0010] and the Michael J. Fox Foundation for Parkinson’s Research [MJFF 02243, MJFF 023427].