As an important target for tumor therapy, heat shock protein 90 has attracted tremendous attention. Through structure analysis, we rationally designed three analogs of VER-50589 which is a known and potent Hsp90 inhibitor. Target inhibitory activity result showed that one compound dubbed as 12–1 exhibited strong inhibitory activity against Hsp90 with an IC₅₀ value of 9 nM. In tumor cell viability experiment, compound 12–1 robustly repressed the proliferation against six human tumor cells with IC₅₀ values all in nanomolar range scoring over VER-50589 and geldanamycin. 12–1 was able to induce apoptosis of tumor cells and arrest the tumor cell cycle in G0/G1 phase. Meanwhile, western blot results showed that 12–1 could significantly downregulated the expression of two Hsp90 client proteins CDK4 and HER2. Finally, molecular dynamic simulation showed that compound 12–1 could fit well with ATP binding site on N-terminal of Hsp90.

热休克蛋白90作为肿瘤治疗的重要靶点引起了极大的关注。通过结构分析，我们合理设计了VER-50589的三种类似物，VER-50589是一种已知的有效Hsp90抑制剂。目标抑制活性结果表明，一种化合物12 – 1对Hsp90表现出很强的抑制活性，IC ₅₀值为9 nM。在肿瘤细胞活力实验中，化合物12 – 1强烈抑制了六种人类肿瘤细胞的增殖，IC ₅₀值均在纳摩尔范围内，评分优于 VER-50589 和格尔德霉素。 12 – 1能够诱导肿瘤细胞凋亡并将肿瘤细胞周期阻滞在G0/G1期。同时，western blot结果显示12-1可以显着下调两个Hsp90客户蛋白CDK4和HER2的表达。最后，分子动力学模拟表明，化合物12-1能够与Hsp90 N端的ATP结合位点很好地吻合。