| Structural highlights
Function
[TTK_HUMAN] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.[1]
Publication Abstract from PubMed
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.
Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity.,Kusakabe KI, 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 J Med Chem. 2015 Feb 10. PMID:25625617[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046
- ↑ Kusakabe KI, 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. Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity. J Med Chem. 2015 Feb 10. PMID:25625617 doi:http://dx.doi.org/10.1021/jm501599u
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