Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 13, Pages 3826-3832Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.04.080
Keywords
Anti-metastasis; Rho; MKL1; SRF; Cancer; Gene transcription inhibitor; Cell migration inhibition
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Funding
- Pharmacological Sciences Training Program grant from NIGMS [GM007767]
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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., Clog 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 mu M) 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. (c) 2013 Elsevier Ltd. All rights reserved.
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