Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies

Eur J Med Chem. 2019 Jul 1:173:44-62. doi: 10.1016/j.ejmech.2019.03.062. Epub 2019 Apr 3.

Abstract

Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC50 of 0.4 nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50: 0.013 μM) and displayed low affinity for hERG (IC50 > 40 μM). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies.

Keywords: CHK1 kinase inhibitor; Hematologic malignancies; Monotherapy; Selectivity.

MeSH terms

  • Checkpoint Kinase 1 / antagonists & inhibitors*
  • Checkpoint Kinase 1 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / metabolism
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • CHEK1 protein, human
  • Checkpoint Kinase 1