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TitleType II kinase inhibitors that target Parkinson's disease-associated LRRK2.
Journal, issue, pagesSci Adv, Vol. 11, Issue 23, Page eadt2050, Year 2025
Publish dateJun 6, 2025
AuthorsNicolai D Raig / Katherine J Surridge / Marta Sanz-Murillo / Verena Dederer / Andreas Krämer / Martin P Schwalm / Nicholas M Lattal / Lewis Elson / Deep Chatterjee / Sebastian Mathea / Thomas Hanke / Andres E Leschziner / Samara L Reck-Peterson / Stefan Knapp /
PubMed AbstractIncreased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have ...Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors. We designed these inhibitors with a combinatorial chemistry approach fusing selective LRRK2 type I and promiscuous type II inhibitors using iterative cycles of synthesis supported by structural biology and activity testing. Our lead compounds are selective and potent toward both LRRK2 and LRRK1, a close relative of LRRK2. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive LRRK2 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.
External linksSci Adv / PubMed:40465731 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 3.65 Å
Structure data

EMDB-47004: Focused refinement map on C-terminal half of LRRK2 (RoC-CORA domains)
Method: EM (single particle) / Resolution: 3.65 Å

47006

9dmi

EMDB-47006, PDB-9dmi:
Structure of the C-terminal half of LRRK2 bound to RN277 (Type-II inhibitor)
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-47025: Focused refinement map on C-terminal half of LRRK2 bound to RN277 (CORB-Kinase-WD40 domains)
Method: EM (single particle) / Resolution: 3.35 Å

PDB-9ez3:
Crystal structure of human CLK3 bound to RN129
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

PDB-1a7q:
FV FRAGMENT OF MOUSE MONOCLONAL ANTIBODY D1.3 (BALB/C, IGG1, K) HIGH AFFINITY EXPRESSED VARIANT CONTAINING SER26L->GLY, ILE29L->THR, GLU81L->ASP, THR97L->SER, PRO240H->LEU, ASP258H->ALA, LYS281H->GLU, ASN283H->ASP AND LEU312H->VAL

ChemComp-SO4:
SULFATE ION

PDB-1h74:
CRYSTAL STRUCTURE OF HOMOSERINE KINASE COMPLEXED WITH ILE

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsPROTEIN BINDING / GTPase / Kinase / inhibitors / TRANSFERASE / CLK3 / Inhibitor / TYPII

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