RRC ID 67417
著者 Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y.
タイトル Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.
ジャーナル J Med Chem
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.
巻・号 58(4)
ページ 1760-75
公開日 2015-2-26
DOI 10.1021/jm501599u
PMID 25625617
MeSH Administration, Oral Animals Antineoplastic Agents / chemical synthesis Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Cell Cycle Proteins / antagonists & inhibitors* Cell Cycle Proteins / metabolism Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Dose-Response Relationship, Drug Drug Discovery* Drug Screening Assays, Antitumor Female Humans Imidazoles / chemical synthesis Imidazoles / chemistry Imidazoles / pharmacology* Mice Mice, Inbred BALB C Mice, Nude Molecular Structure Protein Kinase Inhibitors / administration & dosage Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Protein Serine-Threonine Kinases / antagonists & inhibitors* Protein Serine-Threonine Kinases / metabolism Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / metabolism Pyridazines / chemical synthesis Pyridazines / chemistry Pyridazines / pharmacology* Rats Structure-Activity Relationship
IF 6.205
リソース情報
ヒト・動物細胞 Lu99(RCB1900)