Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer
Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer
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DOI：
10.1016/j.canlet.2018.08.016
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Cherkasov, Artem
中科院分区：
文献类型：
--
作者：
Dalal, Kush;Ban, Fuqiang;Cherkasov, Artem
前列腺癌(PCA)是北美男性的主要死亡原因。雄激素受体(AR)是一种激素可诱导的转录因子，可驱动肿瘤促进基因的表达，是前列腺癌重要的治疗靶点。类固醇重新聚集到其配体结合域(LBD)，然后通过DNA结合域(DBD)进行受体核转位和二聚化，从而激活AR。临床上使用的小分子干扰类固醇的募集和阻止AR驱动的肿瘤生长，但由于LBD突变的出现或缺乏LBD的结构性活性变异的表达，如ARV7，使其无效。这两种耐药机制都扰乱了对以AR信号返回为特征的“去势抵抗”阶段前列腺癌(CRPC)的治疗。在这里，我们利用计算机辅助药物设计来开发阻止AR-DBD二聚化界面的小分子，鉴于其在AR激活和独立于LBD的作用，这是一个有吸引力的靶点。对AR-DBD结构的虚拟筛选导致了阻止AR二聚的原型化合物的开发，通过LBD非依赖的机制抑制AR的转录活性。这些抑制剂可能会潜在地绕过AR依赖的耐药机制，直接靶向CRPC肿瘤的生长。
Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD). Clinically used small molecules interfere with steroid recruitment and prevent AR-driven tumor growth, but are rendered ineffective by emergence of LBD mutations or expression of constitutively active variants, such as ARV7, that lack the LBD. Both drug-resistance mechanisms confound treatment of this 'castration resistant' stage of PCa (CRPC), characterized by return of AR signalling. Here, we employ computer-aided drug-design to develop small molecules that block the AR-DBD dimerization interface, an attractive target given its role in AR activation and independence from the LBD. Virtual screening on the AR-DBD structure led to development of prototypical compounds that block AR dimerization, inhibiting AR-transcriptional activity through a LBD-independent mechanism. Such inhibitors may potentially circumvent AR-dependent resistance mechanisms and directly target CRPC tumor growth.