Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents

Bioorg Med Chem Lett. 2013 Jul 1;23(13):3826-32. doi: 10.1016/j.bmcl.2013.04.080. Epub 2013 May 7.

Abstract

CCG-1423 (1) is a novel inhibitor of Rho/MKL1/SRF-mediated gene transcription that inhibits invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. We recently reported the design and synthesis of conformationally restricted analogs (e.g., 2) with improved selectivity for inhibiting invasion versus acute cytotoxicity. In this study we conducted a survey of aromatic substitution with the goal of improving physicochemical parameters (e.g., ClogP, MW) for future efficacy studies in vivo. Two new compounds were identified that attenuated cytotoxicity even further, and were fourfold more potent than 2 at inhibiting PC-3 cell migration in a scratch wound assay. One of these (8a, CCG-203971, IC50=4.2 μM) was well tolerated in mice for 5 days at 100mg/kg/day i.p., and was able to achieve plasma levels exceeding the migration IC50 for up to 3 h.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Anilides / chemical synthesis
  • Anilides / chemistry
  • Anilides / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Molecular Structure
  • Neoplasm Metastasis / drug therapy
  • Nipecotic Acids / chemical synthesis
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology*
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Serum Response Factor / antagonists & inhibitors*
  • Serum Response Factor / genetics
  • Serum Response Factor / metabolism
  • Structure-Activity Relationship
  • Trans-Activators
  • rhoA GTP-Binding Protein / antagonists & inhibitors*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Amides
  • Anilides
  • Antineoplastic Agents
  • Benzamides
  • CCG 1423
  • DNA-Binding Proteins
  • MRTFA protein, human
  • Nipecotic Acids
  • Oncogene Proteins, Fusion
  • Serum Response Factor
  • Trans-Activators
  • nipecotic acid
  • rhoA GTP-Binding Protein