Targeting the entry region of Hsp90's ATP binding pocket with a novel 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl amide

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.

Cancer; Hsp90; Inhibitor.