2. Academic Validation
  3. Type-II kinase inhibitors that target Parkinson's Disease-associated LRRK2

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

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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