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

J Med Chem. 2017 Nov 9;60(21):8989-9002. doi: 10.1021/acs.jmedchem.7b01223. Epub 2017 Oct 27.

Abstract

Triple 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.

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Female
  • Heterografts
  • Humans
  • Mice
  • Mitosis / drug effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • RNA Splicing / drug effects
  • Structure-Activity Relationship
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / enzymology

Substances

  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • TTK protein, human

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