| Autor: |
Williamson, Douglas S., Smith, Garrick P., Acheson-Dossang, Pamela, Bedford, Simon T., Chell, Victoria, Chen, I-Jen, Daechsel, Justus C. A., Daniels, Zoe, David, Laurent, Dokurno, Pawel, Hentzer, Morten, Herzig, Martin C., Hubbard, Roderick E., Moore, Jonathan D., Murray, James B., Newland, Samantha, Ray, Stuart C., Shaw, Terry, Surgenor, Allan E., Terry, Lindsey, Thirstrup, Kenneth, Wang, Yikang, Christensen, Kenneth V. |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson’s disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC50data for 22were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant structure). Compound 22was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC50values for 22in mouse brain and kidney being 1.3 and 5 nM, respectively. |
| Databáze: |
Supplemental Index |
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