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. 2013 Jul 1;23(13):3826-32.
doi: 10.1016/j.bmcl.2013.04.080. Epub 2013 May 7.

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

Jessica L Bell  1 , Andrew J Haak, Susan M Wade, Paul D Kirchhoff, Richard R Neubig, Scott D Larsen
Affiliations

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

Jessica L Bell et al. Bioorg Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
Figure 2
Figure 2
Effects of new compounds on PC-3 cell migration using a scratch wound assay. A) Example images of the wounds after 24 hours taken with a bright-field inverted microscope (Leica DM IRB, 2.5× magnification). B) Percent inhibition of migration into wound area. Area quantification of the wounds was determined computationally using ImageJ® software (NIH).
Figure 3
Figure 3
Effects of new compounds on PC-3 cell migration. Compounds were tested at various concentrations in a scratch wound assay. IC50 values are in μM.
Scheme 1
Scheme 1
Reagents and conditions: (a) BOC2O, NaOH, H2O, Dioxane; (b) 4-ClPhNH2, EDC, DMAP, DCM; (c) TFA, DCM, −10 °C; (d) i. m-R1PhCO2H, EDC, DMAP, DCM/DMF; ii. Amberlyst-15, DCM.
Scheme 2
Scheme 2
Reagents and conditions: (a) 3,5-bis(CF3)PhCOCl, DIPEA, DCM; (b) LiOH, EtOH; (c) m-R2PhNH2, EDC, DMAP, DCM.
See this image and copyright information in PMC

References

    1. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev. 2005;19(17):1974–9. - PMC - PubMed
    1. Mees C, Nemunaitis J, Senzer N. Transcription factors: their potential as targets for an individualized therapeutic approach to cancer. Cancer Gene Ther. 2009;16(2):103–12. - PubMed
    1. Clark EA, Golub TR, Lander ES, Hynes RO. Genomic analysis of metastasis reveals an essential role for RhoC. Nature. 2000;406(6795):532–5. - PubMed
    1. Sahai E, Marshall CJ. RHO-GTPases and cancer. Nat Rev Cancer. 2002;2(2):133–42. - PubMed
    1. van Golen KL, Wu ZF, Qiao XT, Bao LW, Merajver SD. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 2000;60(20):5832–8. - PubMed

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