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

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.

• Authors: Chris R Evelyn, Jessica L Bell, Jenny G Ryu, Susan M Wade, Andrew Kocab, Nicole L Harzdorf, H D Showalter, Richard R Neubig, Scott D Larsen
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 2 Pg. 665-72 (Jan 15 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 19963382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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