John Hatcher, PhD
Principal Scientist, Medicinal Chemistry Core, Dana-Farber
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Development of Small Molecules and Degraders Targeting LRRK2 for the Treatment of Neurodegenerative Diseases
Project Overview
- LRRK2 is a promising therapeutic target in Parkinson’s disease, yet safety concerns and potent selectivity stalled development of inhibitors and degraders.
- Dana-Farber scientists have developed LRRK2 lead inhibitors and degraders against LRRK2 variants, reducing off-target toxicity.
- Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development.
Technology
Dana-Farber scientists have developed LRRK2 lead inhibitors that bind potently and selectively to LRRK2 variants, while reducing off-target toxicity associated with Type I kinase inhibitors. Moreover, the team also developed LRRK2 lead cell penetrant degraders. The LRRK2 degraders developed show excellent cell penetration, recruitment of CRBN, complete degradation and exceptional specificity towards LRRK2.
Further Details:
- Choi HG, Zhang J, Deng X, Hatcher JM, Patricelli MP, Zhao Z, Alessi DR, Gray NS. Brain Penetrant LRRK2 Inhibitor. ACS Med Chem Lett. 2012 Aug 9;3(8):658-662.
- Hatcher JM, Zhang J, Choi HG, Ito G, Alessi DR, Gray NS. Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor. ACS Med Chem Lett. 2015 Apr 7;6(5):584-9.
- Hatcher JM, Zwirek M, Sarhan AR, Vatsan PS, Tonelli F, Alessi DR, Davies P, Gray NS. Development of a highly potent and selective degrader of LRRK2. Bioorg Med Chem Lett. 2023 Oct 1;94:129449.
Benefits of LRRK2 degraders:
- Cell penetrating capabilities
- Effective recruitment of CRBN
- Complete degradation of LRRK2 wildtype and variants
- Exceptional selectivity
Benefits of LRRK2 inhibitors:
- Potent inhibition of LRRK2 wildtype and variants
- Exceptional selectivity towards LRRK2 wildtype and variants
- Improved physical properties
- Reduced off-target TTK inhibition
Team Members: John Hatcher, PhD, Nathanael S. Gray, PhD
Opportunities
Team Members
Nathanael S. Gray, PhD
Professor of Chemical and Systems Biology, Co-Director of Cancer Drug Discovery, Stanford Medicine
Former Principal Investigator, Dana-Farber
