尽管前列腺癌（PCa）患者最初对雄激素剥夺疗法有反应，但有些患者最终会发展为去势抵抗性前列腺癌（CRPC）。雄激素受体 (AR) 介导的细胞信号传导是 CRPC 进展的主要驱动因素，而只有一小部分 PCa 变为 AR 阴性。本研究旨在了解 PCa 细胞中 N-肉豆蔻酰转移酶对 AR 水平的调节。通过各种方法对两种对映体 (1S,2S)- d-NMAPPD 和 (1R,2R)- d-NMAPPD (LCL4) 进行了表征。 1 H 和 13 C NMR、UHPLC、高分辨率质谱、圆二色性）并使用计算对接分析评估与 N-肉豆蔻酰转移酶 1 (NMT1) 结合的能力。对这些化合物的结构-活性关系分析导致 (1R,2R)-LCL204 的合成，并利用纯化的全长 NMT1 酶将其评估为潜在的 NMT1 抑制剂。 NMT 抑制活性通过点击化学和免疫印迹测定。在异种移植肿瘤模型中评估了 NMT1 对肿瘤生长的调节。(1R,2R)- d-NMAPPD，而不是其对映体 (1S,2S)- d-NMAPPD，抑制 NMT1 活性并降低 AR 蛋白水平。 (1R,2R)-LCL204 是 (1R,2R)-d-NMAPPD 的衍生物，可抑制整体蛋白肉豆蔻酰化。它还抑制 PCa 细胞中 AR 全长或变体的蛋白质水平、核易位和转录活性。这是由于泛素和蛋白酶体介导的 AR 降解增强。敲低 NMT1 水平可抑制肿瘤生长和癌细胞增殖。d-NMAPPD 对 N-肉豆蔻酰转移酶活性的抑制功效是立体特异性的。 (1R,2R)-LCL204 在前列腺癌细胞中以低微摩尔浓度降低整体 N-肉豆蔻酰化和雄激素受体蛋白水平。 NMT1 的药理抑制可增强泛素介导的 AR 蛋白酶体降解。这项研究阐明了 N-肉豆蔻酰转移酶的新功能，并提供了治疗 CRPC 的潜在策略。© 2023 作者。 《前列腺》由 Wiley periodicals LLC 出版。

Even though prostate cancer (PCa) patients initially respond to androgen deprivation therapy, some will eventually develop castration resistant prostate cancer (CRPC). Androgen receptor (AR) mediated cell signaling is a major driver in the progression of CRPC while only a fraction of PCa becomes AR negative. This study aimed to understand the regulation of AR levels by N-myristoyltransferase in PCa cells.Two enantiomers, (1S,2S)- d-NMAPPD and (1R,2R)- d-NMAPPD (LCL4), were characterized by various methods (1 H and 13 C NMR, UHPLC, high-resolution mass spectra, circular dichroism) and evaluated for the ability to bind to N-myristoyltransferase 1 (NMT1) using computational docking analysis. structure-activity relationship analysis of these compounds led to the synthesis of (1R,2R)-LCL204 and evaluation as a potential NMT1 inhibitor utilizing the purified full length NMT1 enzyme. The NMT inhibitory activity wase determined by Click chemistry and immunoblotting. Regulation of NMT1 on tumor growth was evaluated in a xenograft tumor model.(1R,2R)- d-NMAPPD, but not its enantiomer (1S,2S)- d-NMAPPD, inhibited NMT1 activity and reduced AR protein levels. (1R,2R)-LCL204, a derivative of (1R,2R)- d-NMAPPD, inhibited global protein myristoylation. It also suppressed protein levels, nuclear translocation, and transcriptional activity of AR full-length or variants in PCa cells. This was due to enhanced ubiquitin and proteasome-mediated degradation of AR. Knockdown of NMT1 levels inhibited tumor growth and proliferation of cancer cells.Inhibitory efficacy on N-myristoyltransferase activity by d-NMAPPD is stereospecific. (1R,2R)-LCL204 reduced global N-myristoylation and androgen receptor protein levels at low micromolar concentrations in prostate cancer cells. pharmacological inhibition of NMT1 enhances ubiquitin-mediated proteasome degradation of AR. This study illustrates a novel function of N-myristoyltransferase and provides a potential strategy for treatment of CRPC.© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.