2. Academic Validation
  3. Selective Inhibitors of G2019S-LRRK2 Kinase Activity

Selective Inhibitors of G2019S-LRRK2 Kinase Activity

  • J Med Chem. 2020 Dec 10;63(23):14821-14839. doi: 10.1021/acs.jmedchem.0c01243.
Albert W Garofalo 1,  Jessica Bright 1,  Stéphane De Lombaert 1,  Alyssa M A Toda 1,  Kerry Zobel 1,  Daniele Andreotti 2,  Claudia Beato 2,  Silvia Bernardi 2,  Federica Budassi 2,  Laura Caberlotto 2,  Peng Gao 3,  Cristiana Griffante 2,  Xinying Liu 3,  Luisa Mengatto 2,  Marco Migliore 2,  Fabio Maria Sabbatini 2,  Anna Sava 2,  Elena Serra 2,  Paolo Vincetti 2,  Mingliang Zhang 3,  Holly J Carlisle 1
Affiliations

Affiliations

  • 1 ESCAPE Bio, South San Francisco, California 94080, United States.
  • 2 Aptuit, an Evotec Company, Verona 37135, Italy.
  • 3 WuXi AppTec, Tianjin 300456, P. R. China.
PMID: 33197196 DOI: 10.1021/acs.jmedchem.0c01243
Abstract

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.

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