10IA
Structure of CHK1 10-pt. mutant complex with macrocyclic LRRK2 inhibitor compound 12 ((10aS,13aS)-3-cyclopropyl-1-methyl-8-(trifluoromethyl)-3,4,10a,11,13a,14-hexahydro-10H,13H-9,5-(azeno)furo[3,4-k]pyrazolo[4,3-b][1,4,6,10]oxatriazacyclotridecine)
This is a non-PDB format compatible entry.
Summary for 10IA
| Entry DOI | 10.2210/pdb10ia/pdb |
| Descriptor | Serine/threonine-protein kinase Chk1, (10aS,13aS)-3-cyclopropyl-1-methyl-8-(trifluoromethyl)-3,4,10a,11,13a,14-hexahydro-10H,13H-9,5-(azeno)furo[3,4-k]pyrazolo[4,3-b][1,4,6,10]oxatriazacyclotridecine (3 entities in total) |
| Functional Keywords | lrrk2, parkinson's, kinase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34490.57 |
| Authors | |
| Primary citation | Yu, E.C.,Zhou, H.,Yan, X.,Logan, K.M.,Li, D.,Gulati, A.,Poremba, K.E.,Ardolino, M.J.,Su, J.,Xiao, D.,Palte, R.L.,McMinn, S.E.,Nogle, L.M.,Adpressa, D.A.,Burgess, S.A.,Xiong, T.,Otte, K.M.,Chobanian, H.R.,Bass, A.,Lee, S.,Pearson, K.,Messina, E.,Parisi, M.,Barnum, J.,Sobol, Z.,Ciaccio, P.J.,DiMauro, E.F.,Fell, M.J.,Fuller, P.H. Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson's Disease. J.Med.Chem., 2026 Cited by PubMed Abstract: Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder for which treatments are limited. Herein, we describe the invention of a macrocyclic LRRK2 inhibitor lead chemical series. Rigorous application of knowledge-, structure-, and property-based drug design culminated in the discovery of compound , which was profiled extensively before it was determined to be clastogenic, which halted its progression. Parallel optimization of kinome selectivity and PXR activation through structure- and property-based drug design resulted in the discovery of the lead macrocycle compound . This macrocycle boasts a remarkably low projected human QD dose, is nongenotoxic, and achieved encouraging brain penetration in early preclinical models. PubMed: 41906303DOI: 10.1021/acs.jmedchem.6c00238 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.739 Å) |
Structure validation
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