Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity

  • Bioorg Med Chem Lett. 2023 Oct 15:95:129487. doi: 10.1016/j.bmcl.2023.129487.
Albert W Garofalo  1 ,  Jacob Schwarz  2 ,  Kerry Zobel  2 ,  Claudia Beato  3 ,  Silvia Bernardi  3 ,  Federica Budassi  3 ,  Laura Caberlotto  3 ,  Peng Gao  4 ,  Cristiana Griffante  3 ,  Xinying Liu  4 ,  Marco Migliore  3 ,  Feifei Qiao  4 ,  Fabio Maria Sabbatini  3 ,  Anna Sava  3 ,  Mingliang Zhang  4 ,  Holly J Carlisle  2
Affiliations
  • 1. ESCAPE Bio, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 2. ESCAPE Bio, South San Francisco, CA 94080, United States.
  • 3. Aptuit, an Evotec Company, 37135 Verona, Italy.
  • 4. WuXi AppTec, Tianjin 300456, PR China.
PMID: 37734423 DOI: 10.1016/j.bmcl.2023.129487
Abstract

The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.

Keywords
G2019S; Kinase inhibitor; LRRK2; Parkinson’s disease.
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