Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423

Bioorg Med Chem Lett. 2010 Jan 15;20(2):665-72. doi: 10.1016/j.bmcl.2009.11.056. Epub 2009 Nov 18.

Abstract

We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / chemical synthesis
  • Anilides / chemistry*
  • Anilides / toxicity
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / toxicity
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / toxicity
  • Cell Line, Tumor
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / toxicity
  • Humans
  • Male
  • Neoplasm Invasiveness
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / toxicity
  • Prostatic Neoplasms / drug therapy
  • Structure-Activity Relationship
  • Trans-Activators
  • Transcription, Genetic
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Anilides
  • Aniline Compounds
  • Benzamides
  • CCG 1423
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • MRTFA protein, human
  • Oncogene Proteins, Fusion
  • Piperidines
  • Trans-Activators
  • rhoA GTP-Binding Protein