An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.
An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.
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DOI：
10.3390/ijms22042124
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发表时间：
2021-02-20
影响因子：
5.6
通讯作者：
Narayanan R
中科院分区：
文献类型：
--
作者：
Mohler ML;Sikdar A;Ponnusamy S;Hwang DJ;He Y;Miller DD;Narayanan R
自从Huggins等人以来，前列腺癌的传统内分泌治疗一直是针对雄激素受体(AR)信号轴的抑制。发现己烯雌酚(DES；一种雌激素)可产生化学去势和PCa肿瘤消退。雄激素剥夺疗法(ADT)仍然是首选的PCA治疗方法。随着时间的推移，ADT不足会导致去势抵抗PCA(CRPC)，其中AR轴仍然活跃，尽管循环中的雄激素水平被去势了。尽管多代竞争性AR拮抗剂(抗雄激素)被批准和使用，但CRPC由于多种机制迅速出现抗雄激素耐药，主要集中在AR轴上。最近来自多个小组的证据已经确定了AR上的非竞争性或非规范的直接结合位点，这些结合位点可以靶向抑制AR轴。本文讨论了PCA治疗模式的新进展，包括下一代分子到非规范位点、靶向嵌合体的蛋白分解(PROTAC)或选择性AR降解物(SARD)的非规范N端域(NTD)结合。讨论了几个以这些新的非正则位点或具有SARD活性的先导化合物为靶标的化合物。其中许多配体仍处于临床前开发阶段，已出现一些早期临床线索，但仍缺乏成功的晚期临床数据。靶点的广度和多样性为优化的非正则抑制剂和/或SARD将能够克服抗雄激素耐药的CRPC提供了希望。
Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.
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影响因子：
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作者：
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