Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

• DOI: 10.1021/jacs.2c05499
• Publication Date: 2022-08-25T17:53:07Z
• Authors: Xingui Liu; Alexia F. Kaloger...; Sofia Domingos; Nikolai Makukhin; Raja S. Nirujogi; Francois Singh; Natalia Shpiro; Anton Saalfrank; Esther Sammler; Ian G. Ganley; Rui Moreira; Dario R. Alessi; Alessio Ciulli
• Keywords: Penetrant (biochemical)

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 inhibitors, which, however, limitations as inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report development LRRK2 proteolysis targeting chimeras (PROTACs), culminating in discovery degrader XL01126, an alternative strategy. Initial designs and screens PROTACs based ligands E3 ligases von Hippel–Lindau (VHL), Cereblon (CRBN), cellular inhibitor apoptosis (cIAP) identified best degraders containing thioether-conjugated VHL ligand VH101. A second round medicinal chemistry exploration led qualifying XL01126 a fast potent multiple cell lines, DC50 values within 15–72 nM, Dmax ranging from 82 90%, degradation half-lives spanning 0.6 2.4 h. exhibits high permeability forms positively cooperative ternary complex (α = 5.7), compensates substantial loss binary binding affinities LRRK2, underscoring its strong performance cells. Remarkably, orally bioavailable (F 15%) penetrate blood–brain barrier after either oral or parenteral dosing mice. Taken together, these experiments qualify suitable probe study noncatalytic scaffolding functions vitro vivo offer attractive starting point future drug development.