School of Pharmacy, College of Pharmacy, China Medical University, Taichung 40402, Taiwan.
Drug Development Center, China Medical University, Taichung 40402, Taiwan.
Curr Med Chem. 2021;28(26):5431-5446. doi: 10.2174/0929867328666210203204254.
A growing body of evidence suggests that Hsp70, which is overexpressed in human breast tumors, plays a role in tumorigenesis and tumor progression in breast cancer as well as in its aggressive phenotypes. Hsp70 constitutes a potential therapeutic target in the treatment of this disease.
We developed a new series of rhodacyanine-based Hsp70 inhibitors, represented by compounds 1 and 6, in which the cationic pyridin-1-ium or thiazol-3-ium ring of existing Hsp70 inhibitors (e.g., JG-40 and JG-98) was replaced by a corresponding benzo- fused N-heterocycle.
Several lines of evidence suggest that these benzo-fused derivatives may exert their antitumor activities, in part, by targeting Hsp70. These putative inhibitors displayed differential antiproliferative efficacy against breast cancer cells (IC as low as 0.25 μM) versus nontumorigenic MCF-10A breast epithelial cells (IC ≥ 5 μM). This was correlated with the corresponding Hsp70 expression levels. Using a protein refolding assay, we confirmed that these agents effectively inhibited the chaperone activity of Hsp70. Moreover, these inhibitors effectively suppressed the expression of well-known oncogenic client proteins of Hsp70's, including FoxM1, HuR, and Akt, which paralleled their antiproliferative efficacy. Supporting the established role of Hsp70 in regulating protein refolding, these derivatives induced autophagy, as manifested by the conversion of LC3B-I to LC3B-II. Notably, these putative Hsp70 inhibitors did not cause a compensatory elevation in Hsp90 expression, contrasting with the previously reported effects of Hsp90 inhibitors on Hsp70 upregulation.
Together with the finding that compounds 1 and 6 showed improved microsomal stability, these results suggest the translational potential of these putative Hsp70 inhibitors to foster new strategies for cancer therapy. However, whether these benzo-fused rhodacyanines act on kinases or other targets remains unclear. It is currently under investigation.
越来越多的证据表明，热休克蛋白 70（Hsp70）在人类乳腺癌肿瘤中过度表达，在乳腺癌的肿瘤发生和肿瘤进展以及其侵袭性表型中发挥作用。Hsp70 是治疗这种疾病的潜在治疗靶点。
我们开发了一系列新的基于罗丹明的 Hsp70 抑制剂，以化合物 1 和 6 为代表，其中现有 Hsp70 抑制剂（如 JG-40 和 JG-98）的阳离子吡啶-1-鎓或噻唑-3-鎓环被相应的苯并稠合 N-杂环取代。
有几条证据表明，这些苯并稠合衍生物可能通过靶向 Hsp70 发挥其抗肿瘤活性。这些假定的抑制剂对乳腺癌细胞（IC 低至 0.25 μM）表现出不同的抗增殖效力，而对非致瘤性 MCF-10A 乳腺上皮细胞（IC≥5 μM）则没有。这与相应的 Hsp70 表达水平相关。使用蛋白重折叠测定法，我们证实这些试剂有效地抑制了 Hsp70 的伴侣活性。此外，这些抑制剂有效地抑制了 Hsp70 的已知致癌客户蛋白的表达，包括 FoxM1、HuR 和 Akt，这与它们的抗增殖效力平行。支持 Hsp70 在调节蛋白重折叠中的作用，这些衍生物诱导自噬，如 LC3B-I 向 LC3B-II 的转化。值得注意的是，这些假定的 Hsp70 抑制剂不会引起 Hsp90 表达的代偿性升高，这与先前报道的 Hsp90 抑制剂对 Hsp70 上调的影响形成对比。
与化合物 1 和 6 表现出改善的微粒体稳定性的发现一起，这些结果表明这些假定的 Hsp70 抑制剂具有转化为癌症治疗新策略的潜力。然而，这些苯并稠合罗丹明是否作用于激酶或其他靶点尚不清楚。目前正在研究中。
