Type-II kinase inhibitors that target Parkinson's Disease-associated LRRK2

  • bioRxiv. 2025 Feb 13:2024.09.17.613365. doi: 10.1101/2024.09.17.613365.
Nicolai D Raig  1  2  3 ,  Katherine J Surridge  3  4  5 ,  Marta Sanz-Murillo  3  5  6 ,  Verena Dederer  1  2  3 ,  Andreas Krämer  1  2 ,  Martin P Schwalm  1  2 ,  Lewis Elson  1  2 ,  Deep Chatterjee  1  2  3 ,  Sebastian Mathea  1  2  3 ,  Thomas Hanke  1  2 ,  Andres E Leschziner  3  5  6 ,  Samara L Reck-Peterson  3  4  5  7 ,  Stefan Knapp  1  2  3
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2. Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • 4. Department of Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 5. Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • 6. Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
  • 7. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
PMID: 39554022 DOI: 10.1101/2024.09.17.613365
Abstract

Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD). Numerous LRRK2-selective type-I kinase inhibitors have been developed and some have entered clinical trials. In this study, we present the first LRRK2-selective type-II kinase inhibitors. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type-I inhibitors. We designed these inhibitors using a combinatorial chemistry approach fusing selective LRRK2 type-I and promiscuous type-II inhibitors by iterative cycles of synthesis supported by structural biology and activity testing. Our current lead structures are selective and potent LRRK2 inhibitors. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation, and expand the potential therapeutic options for PD.

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