AKR1C3 作为去势抵抗性前列腺癌的靶点。
AKR1C3 as a target in castrate resistant prostate cancer.
机构信息
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6061, USA.
出版信息
J Steroid Biochem Mol Biol. 2013 Sep;137:136-49. doi: 10.1016/j.jsbmb.2013.05.012. Epub 2013 Jun 6.
Abstract
Aberrant androgen receptor (AR) activation is the major driver of castrate resistant prostate cancer (CRPC). CRPC is ultimately fatal and more therapeutic agents are needed to treat this disease. Compounds that target the androgen axis by inhibiting androgen biosynthesis and or AR signaling are potential candidates for use in CRPC treatment and are currently being pursued aggressively. Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis within the prostate. It catalyzes the 17-ketoreduction of weak androgen precursors to give testosterone and 5α-dihydrotestosterone. AKR1C3 expression and activity has been implicated in the development of CRPC, making it a rational target. Selective inhibition of AKR1C3 will be important, however, due to the presence of closely related isoforms, AKR1C1 and AKR1C2 that are also involved in androgen inactivation. We examine the evidence that supports the vital role of AKR1C3 in CRPC and recent developments in the discovery of potent and selective AKR1C3 inhibitors. This article is part of a Special Issue entitled 'CSR 2013'.
摘要
雄激素受体 (AR) 的异常激活是去势抵抗性前列腺癌 (CRPC) 的主要驱动因素。CRPC 最终是致命的，需要更多的治疗药物来治疗这种疾病。通过抑制雄激素生物合成和/或 AR 信号来靶向雄激素轴的化合物是用于 CRPC 治疗的潜在候选药物，目前正在积极研究。醛酮还原酶 1C3 (AKR1C3) 在前列腺内的雄激素生物合成中起着关键作用。它催化弱雄激素前体的 17-酮还原为睾酮和 5α-二氢睾酮。AKR1C3 的表达和活性与 CRPC 的发展有关，使其成为一个合理的靶点。然而，由于存在密切相关的同工酶 AKR1C1 和 AKR1C2，它们也参与雄激素失活，因此选择性抑制 AKR1C3 将非常重要。我们检查了支持 AKR1C3 在 CRPC 中的重要作用的证据，以及发现有效且选择性的 AKR1C3 抑制剂的最新进展。本文是题为“CSR 2013”的特刊的一部分。
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