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8SIW

Structure of Compound 5 bound to the CHK1 10-point mutant

Summary for 8SIW
Entry DOI10.2210/pdb8siw/pdb
DescriptorSerine/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 Keywordslrrk2, parkinson's, kinase, transferase
Biological sourceHomo sapiens (human)
Total number of polymer chains2
Total formula weight69208.47
Authors
Palte, R.L. (deposition date: 2023-04-17, release date: 2023-11-01, Last modification date: 2023-11-15)
Primary citationKattar, 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: 37861679
DOI: 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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