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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Evelyn, Chris R.¹  Bell, Jessica L.²  Ryu, Jenny G.²  Wade, Susan M.¹  Kocab, Andrew¹  Harzdorf, Nicole L.²  Showalter, H. D. Hollis²  Neubig, Richard R.¹  Larsen, Scott D.² 

[1] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Coll Pharm, Dept Med Chem, Ann Arbor, MI 48109 USA

关键词: Metastasis;    RhoA;    Prostate cancer;    Serum response factor;    Serum response element;    Conformational restriction;    Bioisostere;   

DOI  :  10.1016/j.bmcl.2009.11.056

来源: Elsevier

【 摘 要 】

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. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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