We designed and synthesized a series of HECT (homologous to the E6-AP carboxyl terminus) domain binding inhibitors based on indole-3-carbinol (I3C) by structure-based rational drug design. Thermal shift and MTT assays indicated that compound A3 had a good HECT domain binding capacity and potent breast cancer cells inhibition activity, respectively. Subsequent studies showed that compound A3 inhibited proliferation and invasion, induced apoptosis and S-phase cell block. Additionally, compound A3 altered the expression of apoptosis and cell cycle related protein in MDA-MB-231 cells. Finally, computational simulation indicated the proposed binding mode of A3 with the NEDD4–1 HECT domain.

我们通过基于结构的合理药物设计，设计并合成了一系列基于吲哚-3-甲醇 (I3C) 的 HECT（与 E6-AP 羧基末端同源）结构域结合抑制剂。热位移和 MTT 测定表明化合物A3分别具有良好的 HECT 结构域结合能力和有效的乳腺癌细胞抑制活性。随后的研究表明，化合物A3抑制增殖和侵袭，诱导细胞凋亡和S期细胞阻滞。此外，化合物A3改变了MDA-MB-231细胞中凋亡和细胞周期相关蛋白的表达。最后，计算模拟表明了A3与 NEDD4-1 HECT 结构域的拟议结合模式。