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 language | English (US) |
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Journal | Molecules (Basel, Switzerland) |
Volume | 24 |
Issue number | 15 |
DOIs | |
State | Published - 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