3W1F

Crystal structure of Human MPS1 catalytic domain in complex with 5-(5-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-2-methylbenzenesulfonamide

Summary for 3W1F

• Entry DOI: 10.2210/pdb3w1f/pdb
• Related: 3VQU
• Descriptor: Dual specificity protein kinase TTK, 5-[5-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]-2-methylbenzenesulfonamide (3 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: 37269.84

Authors

Kusakabe, K.,Ide, N.,Daigo, Y.,Tachibana, Y.,Itoh, T.,Yamamoto, T.,Hashizume, H.,Hato, Y.,Higashino, K.,Okano, Y.,Sato, Y.,Inoue, M.,Iguchi, M.,Kanazawa, T.,Ishioka, Y.,Dohi, K.,Kido, Y.,Sakamoto, S.,Yasuo, K.,Maeda, M.,Higaki, M.,Ueda, K.,Yoshizawa, H.,Baba, Y.,Shiota, T.,Murai, H.,Nakamura, Y. (deposition date: 2012-11-14, release date: 2013-06-26, Last modification date: 2024-03-20)

Primary citation

Kusakabe, K.,Ide, N.,Daigo, Y.,Tachibana, Y.,Itoh, T.,Yamamoto, T.,Hashizume, H.,Hato, Y.,Higashino, K.,Okano, Y.,Sato, Y.,Inoue, M.,Iguchi, M.,Kanazawa, T.,Ishioka, Y.,Dohi, K.,Kido, Y.,Sakamoto, S.,Yasuo, K.,Maeda, M.,Higaki, M.,Ueda, K.,Yoshizawa, H.,Baba, Y.,Shiota, T.,Murai, H.,Nakamura, Y.
Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125)
J.Med.Chem., 56:4343-4356, 2013

PubMed Abstract: Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

PubMed: 23634759
DOI: 10.1021/jm4000215

Experimental method

X-RAY DIFFRACTION (2.7 Å)