3VQU

CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH 4-[(4-amino-5-cyano-6-ethoxypyridin-2- yl)amino]benzamide

Summary for 3VQU

• Entry DOI: 10.2210/pdb3vqu/pdb
• Descriptor: Dual specificity protein kinase TTK, IODIDE ION, 4-[(4-amino-5-cyano-6-ethoxypyridin-2-yl)amino]benzamide, ... (4 entities in total)
• Functional Keywords: kinase, serine/threonine-protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38039.71

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. (deposition date: 2012-03-30, release date: 2012-06-27, Last modification date: 2024-03-20)

Primary citation

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.
Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.
Acs Med.Chem.Lett., 3:560-564, 2012

PubMed Abstract: 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.

PubMed: 24900510
DOI: 10.1021/ml3000879

Experimental method

X-RAY DIFFRACTION (2.4 Å)