A Structure-Activity Relationship Study of Bis-Benzamides as Inhibitors of Androgen Receptor-Coactivator Interaction

Tae Kyung Lee, Preethi Ravindranathan, Rajni Sonavane, Ganesh V. Raj, Jung Mo Ahn

Research output: Contribution to journalArticlepeer-review

Abstract

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR-coactivator interaction, we have designed and synthesized a series of bis-benzamides by modifying functional groups at the N/C-terminus and side chains. A structure-activity relationship study showed that the nitro group at the N-terminus of the bis-benzamide is essential for its biological activity while the C-terminus can have either a methyl ester or a primary carboxamide. Surveying the side chains with various alkyl groups led to the identification of a potent compound 14d that exhibited antiproliferative activity (IC50 value of 16 nM) on PCa cells. In addition, biochemical studies showed that 14d exerts its anticancer activity by inhibiting the AR-PELP1 interaction and AR transactivation.

Original languageEnglish (US)
JournalMolecules (Basel, Switzerland)
Volume24
Issue number15
DOIs
StatePublished - Jul 31 2019

Keywords

  • androgen receptor
  • bis-benzamide scaffold
  • coactivator PELP1
  • prostate cancer
  • protein–protein interaction
  • α-helix mimetics

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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