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.
Highlights
Prostate cancer (PCa) is one of the leading causes of cancer death worldwide, accounting for an estimated 1.28 million new cases and 358,000 deaths in 2018 [1]
We previously developed oligo-benzamideα-helix mimetics that can place its substituents in the same spatial arrangement found in an α-helix, based α-helix mimetics that can place its substituents in the same spatial arrangement found in an αthereby reproducing the structure and function of the helix [15]
For the structure–activity relationship study, we focused on three positions in the structure of the bis-benzamide D2: the N-terminal nitro group, the C-terminal methyl ester, and two isobutyl the bis-benzamide D2: the N-terminal nitro group, the C-terminal methyl ester, and two isobutyl substituents at the O-alkylated side chains (Figure 1)
Summary
Prostate cancer (PCa) is one of the leading causes of cancer death worldwide, accounting for an estimated 1.28 million new cases and 358,000 deaths in 2018 [1]. Various strategies have been developed to deprive androgens or block their effects. Surgical or chemical castration suppresses PCa growth by lowering circulating androgen levels. Chemical castration is achieved by blocking testicular and adrenal androgen synthesis with luteinizing hormone-releasing hormone (LH-RH) analogues [4]. Antiandrogens have been developed to inhibit AR activities by competitively blocking androgens from binding to AR LBD [3]. Antiandrogens are initially effective to suppress tumor growth, PCa turns into an incurable androgen-resistant state [5]. The transition to androgen-resistant state frequently involves AR mutations, overexpression of AR and its splice variants, increased production of intratumoral androgens, upregulation of AR coactivators and so on [5,6]
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