Discovery of second generation heat shock protein 110 (HSP110) inhibitors for potential treatment of colorectal cancer

Heat shock protein 110 (HSP110) is an emerging biological target for development of drug to treat colorectal cancer. In the present study, we designed and synthesized a series of novel small-molecule inhibitors of HSP110 based on previously reported HSP110 modulator (hit 1). Among the novel compounds, molecule 7 exhibited the most improved biological activity in vitro and anticancer efficacy in vivo. It exerted greater anti-proliferative potency against several colorectal cancer cells including HCT116 and SW480 with IC50 values of 11.59 ​μM and 6.05 ​μM, respectively. Molecular docking experiment of 7 with HSP110 protein revealed it bound well with the target in the similar way as compound 1. Mechanistic studies revealed that 7 effectively inhibited STAT3 activity and the expression of STAT3 downstream genes, VEGF, MMP7, MMP9. Moreover, 7 significantly abolished IL-6-induced epithelial-mesenchymal transition (EMT) in HCT116 and SW480 ​cells. Finally, 7 exhibited stronger tumor growth inhibition than lead compound 1 ​at the dose of 5 ​mg/kg (i.p.) in an in vivo HCT116 ​cells xenografted nude mice model. Taken together, we identified 7 as 2nd generation of HSP110 inhibitor which exerts remarkable anti-colorectal cancer activities. This compound might serve as a new lead for developing anti-cancer drugs to treat colorectal cancer.