The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC₅₀ = 50.3 nM). Furthermore, it effectively inhibits the proliferation of H1975 non-small cell lung cancer (NSCLC) and Skbr3 breast cancer cell lines with GI₅₀ values of 0.31 μM and 0.11 μM, respectively. Compound 19 induces the degradation of the Hsp90 client proteins including EGFR, Her2, Met, c-Raf, and Akt, and consequently promotes apoptotic cancer cell death. Compound 19 also inhibits the growth of H1975 xenografts in NOD-scid IL2R gamma^null mice without any apparent body-weight loss. The immunohistologic evaluation indicates that compound 19 decreases the expression of Akt in xenograft tumor tissue via an inhibition of the Hsp90 chaperon function. Additionally, the cytochrome P450 assay indicates that compound 19 has no effect on the activities of five major P450 isoforms (IC₅₀ > 50 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between compound 19 and the substrate drugs of the five major P450 isoforms are not expected. Overall, compound 19 represents a new class of Hsp90 inhibitor with its 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl-amide structure, and it has the therapeutic potential to overcome drug resistance in cancer chemotherapy.

分子伴侣Hsp90通过调节多种致癌蛋白的成熟和稳定化，在癌细胞的存活和增殖中起着重要作用。由于Hsp90具有同时禁用多种信号传导途径的潜力，因此已成为癌症治疗的有吸引力的治疗靶标。在这项研究中，描述了一系列Hsp90抑制剂的设计，合成和生物学评估。在合成化合物中，6,7-二氢噻吩并[3,2-c]吡啶-5（4H）-基酰胺19在荧光偏振（FP）结合测定（IC）中对Hsp90的N-末端表现出显着的结合亲和力。₅₀ = 50.3 nM）。此外，它有效抑制了GI ₅₀值分别为0.31μM和0.11μM的H1975非小细胞肺癌（NSCLC）和Skbr3乳腺癌细胞系的增殖。化合物19诱导Hsp90客户蛋白（包括EGFR，Her2，Met，c-Raf和Akt）降解，从而促进凋亡性癌细胞死亡。化合物19还抑制NOD突变的IL2Rγ^无效小鼠中H1975异种移植物的生长，而没有任何明显的体重减轻。免疫组化评估表明化合物19通过抑制Hsp90伴侣功能来降低异种移植肿瘤组织中Akt的表达。此外，细胞色素P450分析表明化合物19对五种主要P450亚型的活性没有影响（ 1A2、2C9、2C19、2D6和3A的IC ₅₀ > 50μM），表明化合物19与底物之间的临床相互作用五种主要P450异构体的药物预计不会出现。总体而言，化合物19以其6,7-二氢噻吩并[3,2-c]吡啶5-5（4H）-基酰胺结构代表了一类新的Hsp90抑制剂，具有克服癌症化疗耐药性的治疗潜能。 。