PDBsum entry 3w1f

Transferase/transferase inhibitor

PDB id: 3w1f

Contents

Protein chain

259 a.a.

Ligands

1O5

Waters ×7

PDB id:

3w1f

Name:

Transferase/transferase inhibitor

Title:

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

Structure:

Dual specificity protein kinase ttk. Chain: a. Fragment: catalytic domain, residues 516-820. Synonym: phosphotyrosine picked threonine-protein kinase, pyt. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ttk, mps1, mps1l1. Expressed in: cell-free synthesis.

Resolution:

2.70Å R-factor: 0.237 R-free: 0.277

Authors:

K.Kusakabe,N.Ide,Y.Daigo,Y.Tachibana,T.Itoh,T.Yamamoto,H.Hashizume, Y.Hato,K.Higashino,Y.Okano,Y.Sato,M.Inoue,M.Iguchi,T.Kanazawa, Y.Ishioka,K.Dohi,Y.Kido,S.Sakamoto,K.Yasuo,M.Maeda,M.Higaki,K.Ueda, H.Yoshizawa,Y.Baba,T.Shiota,H.Murai,Y.Nakamura

Key ref:

K.Kusakabe et al. (2013). Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125). J Med Chem, 56, 4343-4356. PubMed id: 23634759 DOI: 10.1021/jm4000215

Date:

14-Nov-12 Release date: 26-Jun-13

Protein chain

P33981  (TTK_HUMAN) -  Dual specificity protein kinase TTK from Homo sapiens

Seq: 857 a.a.

Struc: 259 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.12.1 - dual-specificity kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
  3. L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm4000215

J Med Chem 56:4343-4356 (2013)

PubMed id: 23634759

Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125).

K.Kusakabe, N.Ide, Y.Daigo, Y.Tachibana, T.Itoh, T.Yamamoto, H.Hashizume, Y.Hato, K.Higashino, Y.Okano, Y.Sato, M.Inoue, M.Iguchi, T.Kanazawa, Y.Ishioka, K.Dohi, Y.Kido, S.Sakamoto, K.Yasuo, M.Maeda, M.Higaki, K.Ueda, H.Yoshizawa, Y.Baba, T.Shiota, H.Murai, Y.Nakamura.

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.