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Ref Type Journal Article
PMID (24900510)
Authors Kusakabe K, Ide N, Daigo Y, Itoh T, Higashino K, Okano Y, Tadano G, Tachibana Y, Sato Y, Inoue M, Wada T, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Tagashira S, Kido Y, Sakamoto S, Yasuo K, Maeda M, Yamamoto T, Higaki M, Endoh T, Ueda K, Shiota T, Murai H, Nakamura Y
Title Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.
Journal Vol Issue Date Pages Journal Short Title
ACS medicinal chemistry letters 3 7 2012 Jul 12 560-4 ACS Med Chem Lett
URL
Abstract Text Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SNG12 SNG12 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SNG12 MPS1 Inhibitor 27 SNG12, Shionogi compound 12, is a selective inhibitor of TTK (MPS1) that prevents cell proliferation (PMID: 24900510).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References