Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as a promising therapeutic target for human cancer. Up to now, two small molecule PRMT5 inhibitors has been put into phase I clinical trial. In the present study, a series of candidate molecules were designed by combining key pharmacophores of formerly reported PRMT5 inhibitors. The in vitro PRMT5 inhibitory testing of compound 4b14 revealed an IC₅₀ of 2.71 μM, exhibiting high selectivity over PRMT1 and PRMT4 (>70-fold selective). As expected, 4b14 exhibited potent anti-proliferative activity against a panel of leukemia and lymphoma cells, including MV4-11, Pfeiffer, SU-DHL-4 and KARPAS-422. Besides, 4b14 showed significant cell cycle arrest and apoptosis-inducing effects, as well as reduced the cellular symmetric arginine dimethylation level of SmD3 protein. Finally, affinity profiling analysis indicated that hydrophobic interactions, π-π stacking and cation-π actions made the major contributions to the overall binding affinity. This scaffold provides a new chemical template for further development of better lead compounds targeting PRMT5.

蛋白质精氨酸甲基转移酶5（PRMT5）是一种与表观遗传学相关的酶，已被证实可作为人类癌症的有希望的治疗靶标。到目前为止，两种小分子PRMT5抑制剂已进入I期临床试验。在本研究中，通过结合先前报道的PRMT5抑制剂的关键药效​​团设计了一系列候选分子。在体外化合物的抑制PRMT5测试4b14显示的IC ₅₀为2.71μM，表现出超过PRMT1和PRMT4（> 70倍的选择性）高选择性。如预期的那样，4b14对一组白血病和淋巴瘤细胞（包括MV4-11，Pfeiffer，SU-DHL-4和KARPAS-422）表现出有效的抗增殖活性。此外，4b14显示出显着的细胞周期停滞和凋亡诱导作用，以及降低了SmD3蛋白的细胞对称精氨酸二甲基化水平。最后，亲和力分析表明疏水相互作用，π-π堆积和阳离子-π作用对整体结合亲和力起主要作用。该支架为进一步开发针对PRMT5的更好的铅化合物提供了新的化学模板。