title: Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
abstract: Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
authors.affiliation: Medicinal Research Laboratories, ‡Drug Developmental Research Laboratories, and §Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center , 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kusakabe
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ide
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashizume
authors.forename: Kohei
authors.initials: K
authors.lastname: Nozu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Genta
authors.initials: G
authors.lastname: Tadano
authors.forename: Sachie
authors.initials: S
authors.lastname: Tagashira
authors.forename: Kenichi
authors.initials: K
authors.lastname: Higashino
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Okano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.forename: Makiko
authors.initials: M
authors.lastname: Inoue
authors.forename: Motofumi
authors.initials: M
authors.lastname: Iguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Ishioka
authors.forename: Keiji
authors.initials: K
authors.lastname: Dohi
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kido
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ando
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.forename: Masayo
authors.initials: M
authors.lastname: Higaki
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Baba
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007093:Imidazoles; C000597468:N-cyclopropyl-4-(8-((tetrahydro-2H-pyran-4-yl)methylamino)-6-(1,1,1-trifluoro-2-methylpropan-2-ylamino)imidazo(1,2-b)pyridazin-3-yl)benzamide; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human