title: Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents.
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.
authors.affiliation: Vahlteich Medicinal Chemistry Core, Department of Medicinal Chemistry, College of Pharmacy, MI, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Bell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Haak
authors.forename: Susan M
authors.initials: SM
authors.lastname: Wade
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kirchhoff
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009557:Nipecotic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; C523455:CCG 1423; D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; D009557:Nipecotic Acids; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; C030278:nipecotic acid; D020742:rhoA GTP-Binding Protein