发现并评估一种新型的针对CARM1/HDAC2的双靶抑制剂，作为抗前列腺癌药物的候选化合物。
Discovery and biological evaluation of novel CARM1/HDAC2 dual-targeting inhibitors with anti-prostate cancer agents.
发表日期：2023 Dec
作者：
Sudong Liang, Yifei Geng, Miao-Miao Niu, Yan Zhang, Weiping He, Jindong Li, Li Yang, Zhen Xu
来源：
J Enzym Inhib Med Ch
摘要：
前列腺癌（PCa）是一种临床上异质性严重的疾病，发病率逐渐增加。同时抑制辅因子相关的精氨酸甲基转移酶1（CARM1）和组蛋白去乙酰化酶2（HDAC2）可能成为一种新的对抗PCa的策略。在此，我们通过基于结构的虚拟筛选，鉴定出七种同时作用于CARM1和HDAC2的化合物。这些化合物在体外表现出纳摩尔水平的强大抑制活性。其中，CH-1是最活跃的抑制剂，对CARM1（IC50 = 3.71 ± 0.11 nM）和HDAC2（IC50 = 4.07 ± 0.25 nM）都表现出优异且平衡的抑制效果。分子动力学模拟表明，CH-1可以稳定地结合CARM1和HDAC2的活性口袋。值得注意的是，CH-1对多种与前列腺相关的肿瘤细胞表现出很强的抗增殖活性（IC50 < 1 µM）。体内评估显示，CH-1在DU145移植瘤模型中明显抑制了肿瘤生长。总体而言，CH-1可能是一种有前景的前列腺癌治疗药物候选物。
Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro. Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC50 = 3.71 ± 0.11 nM) and HDAC2 (IC50 = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC50 < 1 µM). In vivo, assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.