CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells

Abstract

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (Kd) constant of 27 ± 2.3 nM. It also exhibits potent in vitro antiproliferative effects in a range of solid tumor cells. In MCF-7 cells with high Hsp90 expression, CPUY201112 induces the degradation of Hsp90 client proteins including HER-2, Akt, and c-RAF. We prove that treating MCF-7 cells with CPUY201112 results in cell cycle arrest and apoptosis through the wild-type (wt) p53 pathway. CPUY201112 also synergizes with Nutlin-3a to induce cancer cell apoptosis. CPUY201112 significantly inhibited the growth of MCF-7 xenografts in nude mice without apparent body weight loss. These results demonstrate that CPUY201112 is a novel Hsp90 inhibitor with potential use in treating wild-type p53 related cancers.

Novel Natural Product-like Caged Xanthones Bearing a Carbamate Moiety Exhibit Antitumor Potency and Anti-Angiogenesis Activity In vivo

“…The inhibition of tumour cell growth was measured by a modified tetrazolium (MTT) salt assay, as previously described 39 . Cells were cultured in a 96-well plate and treated with culture medium alone or different concentrations of the compounds.…”

“…To measure the Hsp90 ATPase activity, a ADP Hunter Plus Assay kit from DiscoverX was used as previously described 39 . Recombinant human Hsp90 protein (200 nM/L, Stressgen) and compounds at different concentrations were pre-incubated in a 384-well black microplate at 37 °C for 0.5 h in the presence of assay buffer from the kit.…”

α-Glucosidase inhibitors from Chinese bayberry (Morella rubraSieb. et Zucc.) fruit: molecular docking and interaction mechanism of flavonols with different B-ring hydroxylations

“…Binding kinetic analysis of myricetin to a-glucosidase was determined by ForteBio Octet K2 system according to Xu et al 33 with minor modications. First, a-glucosidase was incubated with biotin.…”

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

“…It has been reported that inhibiting HSP90 results in upregulation of HSP70 in cells ( 67 , 68 ). HSP90 inhibitors do not generally change the expression of the HSP90 protein, but they inhibit its activity by binding at the N-terminal catalytic ATP-binding site ( 36 , 37 , 54 , 69 ). To further understand the mechanism by which HSP90 inhibitors reverse the NPC1 mutant phenotype, we measured the expression of HSP90, HSP70, and HSP40 as well as the NPC1 protein.…”