Hedgehog pathway inhibitors of the acylthiourea and acylguanidine class show antitumor activity on colon cancer in vitro and in vivo

Eur J Med Chem. 2018 Sep 5:157:368-379. doi: 10.1016/j.ejmech.2018.07.053. Epub 2018 Jul 27.

Abstract

Small series of acylguanidine and acylthiourea derivatives were synthesized in gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized to further development with the perspective of clinical studies.

Keywords: ADME-Tox; Acylguanidine; Gram-scale synthesis; Hedgehog inhibitor; In vivo pharmacokinetics; LS180 xenograft.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Guanidine / administration & dosage
  • Guanidine / chemistry
  • Guanidine / pharmacology*
  • Hedgehog Proteins / antagonists & inhibitors*
  • Hedgehog Proteins / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Structure
  • NIH 3T3 Cells
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Structure-Activity Relationship
  • Thiourea / administration & dosage
  • Thiourea / chemistry
  • Thiourea / pharmacology*

Substances

  • Antineoplastic Agents
  • Hedgehog Proteins
  • Thiourea
  • Guanidine