Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2070-2075. doi: 10.1016/j.bmcl.2019.07.015. Epub 2019 Jul 9.

Abstract

Transforming growth factor (TGF-β), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a-g) and thieno[3,2-c]-pyridin-2-yl imidazoles (20a-g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC50 = 0.008 μM) against ALK5 kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157299 (IC50 = 0.129 μM) and EW-7197 (IC50 = 0.014 μM), respectively. Compound 14g (350) showed the highest selectivity index of ALK5 against p38α MAP kinase, which was significantly higher than that of positive control compounds LY-2157299 (4) and EW-7197 (211). The inhibitory effects of compound 14c on TGF-β-induced Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors.

Keywords: ADMET; ALK5; Imidazole; Inhibitors; TGF-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Pyridines / chemical synthesis
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / pharmacology*
  • Thiophenes / chemical synthesis
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology*

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Pyridines
  • Thiadiazoles
  • Thiophenes
  • Mitogen-Activated Protein Kinase 14
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human