title: Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125).
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.
authors: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. kenichi.kusakabe@shionogi.co.jp
authors: Ken-ichi
authors: K
authors: Kusakabe
authors: Nobuyuki
authors: N
authors: Ide
authors: Yataro
authors: Y
authors: Daigo
authors: Yuki
authors: Y
authors: Tachibana
authors: Takeshi
authors: T
authors: Itoh
authors: Takahiko
authors: T
authors: Yamamoto
authors: Hiroshi
authors: H
authors: Hashizume
authors: Yoshio
authors: Y
authors: Hato
authors: Kenichi
authors: K
authors: Higashino
authors: Yousuke
authors: Y
authors: Okano
authors: Yuji
authors: Y
authors: Sato
authors: Makiko
authors: M
authors: Inoue
authors: Motofumi
authors: M
authors: Iguchi
authors: Takayuki
authors: T
authors: Kanazawa
authors: Yukichi
authors: Y
authors: Ishioka
authors: Keiji
authors: K
authors: Dohi
authors: Yasuto
authors: Y
authors: Kido
authors: Shingo
authors: S
authors: Sakamoto
authors: Kazuya
authors: K
authors: Yasuo
authors: Masahiro
authors: M
authors: Maeda
authors: Masayo
authors: M
authors: Higaki
authors: Kazuo
authors: K
authors: Ueda
authors: Hidenori
authors: H
authors: Yoshizawa
authors: Yoshiyasu
authors: Y
authors: Baba
authors: Takeshi
authors: T
authors: Shiota
authors: Hitoshi
authors: H
authors: Murai
authors: Yusuke
authors: Y
authors: Nakamura
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D018797:Cell Cycle Proteins; D007093:Imidazoles; C432165:pyrazolanthrone; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C075840:TTK protein, human