Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-2016)

ABSTRACT

Introduction: Leucine-rich repeat kinase 2 (LRRK2) is a member of the Tyrosine Kinase-Like (TKL) branch of the kinome tree and is a multi-domain protein that includes GTPase and kinase activity. While genome-wide association studies (GWAS) has linked LRRK2 with Crohn’s disease and leprosy, it has received the greatest attention due to it being implicated as one of the genetic loci associated with autosomal dominant inheritance in Parkinson’s disease (PD).

Areas covered: In this review, the small molecule patent literature from 2014–2016 with a focus on composition of matter and use patents was surveyed. Scifinder was primarily searched using ‘LRRK2ʹ as the query to identify all relevant literature and then triaged for small molecule patents.

Expert opinion: The patent landscape around LRRK2 continues to develop. The early patents covered using existing kinase inhibitors for use against LRRK2. This evolved to compounds specifically designed for selectivity against LRRK2, but key exemplified compounds lacked sufficient brain exposure to affect sufficient efficacy. More recent compounds have addressed this deficiency and show greater potential for treating PD. While potency will be necessary to generate medicines with low human daily doses, brain penetration and safety will be the key differentiators for ultimately determining the most effective LRRK2 disease-modifying treatment for PD.

KEYWORDS:

• Leucine-rich repeat kinase 2
• LRRK2
• kinase
• inhibitors
• Parkinson’s disease

Article highlights

• Leucine-rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson’s disease (PD), Crohn’s disease, leprosy, and some cancer types

• LRRK2 mutations, particularly G2019S, appear to increase the kinase activity, thus the interest in kinase inhibitors for the potential for disease modification in PD

• Overall safety and brain availability of these compounds will require discipline from the medicinal chemist in the design of kinase inhibitors for a CNS indication

• While great progress has been made in the development of potent, brain penetrant, and safe tools compounds, the PD community is awaiting the identification of a clinical candidate

This box summarizes key points contained in the article.

Acknowledgments

The author would like to thank Dr Melinda Gugelchuk and Dr Travis Wager for helpful comments and critical review of this manuscript.

Declaration of interest

The author is a Pfizer employee. The author has no other 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 apart from those disclosed.

Additional information

Funding

No funding to declare.