Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2)

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however have limitations as the inhibited pro-tein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we report the devel-opment of LRRK2 Proteolysis Targeting Chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2 targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases VHL, CRBN and cIAP identified the best degraders containing thioether-conjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC50 values within 15-72 nM, Dmax values range from 82-90%, and degradation half-lives span from 0.6h to2.4h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α=5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F=15%) and can penetrate the blood brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study non-catalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development.