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

Jessica L. Bell, Andrew J. Haak, Susan M. Wade, Paul D. Kirchhoff, Richard R. Neubig, Scott D. Larsen

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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., C log P, 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 100 mg/kg/day i.p., and was able to achieve plasma levels exceeding the migration IC50 for up to 3 h.

Original languageEnglish (US)
Pages (from-to)3826-3832
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number13
DOIs
StatePublished - Jul 1 2013

Keywords

  • Anti-metastasis
  • Cancer
  • Cell migration inhibition
  • Gene transcription inhibitor
  • MKL1
  • Rho
  • SRF

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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