6b4w
TTK in Complex with InhibitorTTK in Complex with Inhibitor
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 PubMedTriple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy. The discovery of a dual TTK protein kinase/ CDC2-like kinase (CLK2) inhibitor for the treatment of triple negative breast cancer initiated from a phenotypic screen.,Riggs JR, Nagy M, Elsner J, Erdman P, Cashion D, Robinson D, Harris R, Huang D, Tehrani L, Deyanat-Yazdi G, Narla RK, Peng X, Tran T, Barnes L, Miller T, Katz J, Tang Y, Chen M, Moghaddam MF, Bahmanyar S, Pagarigan B, Delker SL, LeBrun L, Chamberlain PP, Calabrese A, Canan SS, Leftheris K, Zhu D, Boylan JF J Med Chem. 2017 Oct 9. doi: 10.1021/acs.jmedchem.7b01223. PMID:28991472[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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