4W8D

Crystal structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06454589).

Summary for 4W8D

• Entry DOI: 10.2210/pdb4w8d/pdb
• Related: 4W8E
• Descriptor: Serine/threonine-protein kinase 24 36 kDa subunit, 5-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (3 entities in total)
• Functional Keywords: mst3, pyrrolopyrimidine, kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9Y6E0
• Total number of polymer chains: 1
• Total formula weight: 33239.09

Authors

Jasti, J.,Song, X.,Griffor, M.,Kurumbail, R.G. (deposition date: 2014-08-24, release date: 2015-03-18, Last modification date: 2024-11-20)

Primary citation

Henderson, J.L.,Kormos, B.L.,Hayward, M.M.,Coffman, K.J.,Jasti, J.,Kurumbail, R.G.,Wager, T.T.,Verhoest, P.R.,Noell, G.S.,Chen, Y.,Needle, E.,Berger, Z.,Steyn, S.J.,Houle, C.,Hirst, W.D.,Galatsis, P.
Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.
J.Med.Chem., 58:419-432, 2015

PubMed Abstract: Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.

PubMed: 25353650
DOI: 10.1021/jm5014055

Experimental method

X-RAY DIFFRACTION (1.77 Å)