Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma,Journal of Medicinal Chemistry

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Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-04-04 , DOI: 10.1021/acs.jmedchem.3c02265
Zhihao Liu ₁ , Min Lin ₁ , Chenyu Liu ₂ , Xin Chen ₁ , Qian Chen ₁ , Xinyu Li ₃ , Xiaoyan Wu ₃ , Yahui Wang ₄ , Lei Wang ₁ , Fan Yang ₂ , Cheng Luo _{3,

5} , Jia Jin ₁ , Fei Ye ₁

Affiliation

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC₅₀ = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.

中文翻译：

开发 (2-(苄氧基)苯基)甲胺衍生物作为 CARM1 的有效和选择性抑制剂来治疗黑色素瘤

共激活剂相关精氨酸甲基转移酶 1 (CARM1) 是 I 型蛋白精氨酸甲基转移酶 (PRMT) 的重要成员，已成为多种癌症类型的有前景的治疗靶点。在我们之前的研究中，我们鉴定了一系列 I 型 PRMT 抑制剂，其中 ZL-28-6 ( 6 ) 对 CARM1 的活性增加，而对其他 I 型 PRMT 的活性降低。在这项工作中，我们对化合物6进行了化学修饰，得到了一系列 (2-(苄氧基)苯基)甲胺衍生物作为 CARM1 的有效抑制剂。其中，化合物17e对 CARM1 显示出显着的效力和选择性 (IC ₅₀ = 2 ± 1 nM)，并对黑色素瘤细胞系具有显着的抗增殖作用。细胞热位移测定和蛋白质印迹实验证实，化合物6有效靶向细胞内的 CARM1。此外，化合物17e在黑色素瘤异种移植模型中表现出良好的抗肿瘤功效，表明该化合物值得作为潜在的抗癌剂进行进一步研究。

更新日期：2024-04-04

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