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

• Published in: Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.665-672
• Main Authors: Evelyn, Chris R., Bell, Jessica L., Ryu, Jenny G., Wade, Susan M., Kocab, Andrew, Harzdorf, Nicole L., Hollis Showalter, H.D., Neubig, Richard R., Larsen, Scott D.
• Format: Article
• Language: English
• Subjects: Anilides - chemical synthesis; Anilides - chemistry; Anilides - toxicity; Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - toxicity; Antineoplastic agents; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - toxicity; Bioisostere; Biological and medical sciences; Cell Line, Tumor; Conformational restriction; 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; General aspects; Humans; Male; Medical sciences; Metastasis; Neoplasm Invasiveness; Oncogene Proteins, Fusion - antagonists & inhibitors; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - toxicity; Prostate cancer; Prostatic Neoplasms - drug therapy; RhoA; rhoA GTP-Binding Protein - antagonists & inhibitors; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Serum response element; Serum response factor; Structure-Activity Relationship; Trans-Activators; Transcription, Genetic
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.11.056

Conformational restriction and bioisosteric amide replacement were used to generate novel analogs of the Rho-transcriptional pathway inhibitor CCG-1423. Two compounds were found with significantly improved selectivity for inhibition of PC-3 cancer cell invasion versus cytotoxicity. 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.