8SIW
Structure of Compound 5 bound to the CHK1 10-point mutant
Summary for 8SIW
Entry DOI | 10.2210/pdb8siw/pdb |
Descriptor | Serine/threonine-protein kinase Chk1, (1S,2S)-N-(7-chloro-6-{1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl}isoquinolin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (3 entities in total) |
Functional Keywords | lrrk2, parkinson's, kinase, transferase |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 2 |
Total formula weight | 69208.47 |
Authors | Palte, R.L. (deposition date: 2023-04-17, release date: 2023-11-01, Last modification date: 2023-11-15) |
Primary citation | Kattar, S.D.,Gulati, A.,Margrey, K.A.,Keylor, M.H.,Ardolino, M.,Yan, X.,Johnson, R.,Palte, R.L.,McMinn, S.E.,Nogle, L.,Su, J.,Xiao, D.,Piesvaux, J.,Lee, S.,Hegde, L.G.,Woodhouse, J.D.,Faltus, R.,Moy, L.Y.,Xiong, T.,Ciaccio, P.J.,Pearson, K.,Patel, M.,Otte, K.M.,Leyns, C.E.G.,Kennedy, M.E.,Bennett, D.J.,DiMauro, E.F.,Fell, M.J.,Fuller, P.H. Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease. J.Med.Chem., 66:14912-14927, 2023 Cited by PubMed Abstract: Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound , which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate . This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies. PubMed: 37861679DOI: 10.1021/acs.jmedchem.3c01486 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.877 Å) |
Structure validation
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