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|Ref Type||Journal Article|
|Authors||Xu XL, Bao QC, Jia JM, Liu F, Guo XK, Zhang MY, Wei JL, Lu MC, Xu LL, Zhang XJ, You QD, Sun HP|
|Title||CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells.|
|Date||2016 Jan 08|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CPUY201112||HSP90 Inhibitor 35||CPUY201112 is an N-terminal Hsp90 inhibitor, which leads to decreased expression of Hsp90 client proteins and may result in increased tumor cell apoptosis (PMID: 26743233).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 wild-type||colon cancer||sensitive||CPUY201112||Preclinical||Actionable||In a preclinical study, CPUY201112 reduced viability and induced apoptosis in a colon cancer cell line with wild-type TP53 in culture, and had a limited effect on a colon cancer cell line lacking TP53 (PMID: 26743233).||26743233|
|TP53 wild-type||osteosarcoma||sensitive||CPUY201112||Preclinical||Actionable||In a preclinical study, CPUY201112 reduced viability and induced apoptosis in an osteosarcoma cell line with wild-type TP53 in culture, and had a limited effect on an osteosarcoma cell line lacking TP53 (PMID: 26743233).||26743233|
|TP53 loss||osteosarcoma||decreased response||CPUY201112||Preclinical||Actionable||In a preclinical study, an osteosarcoma cell line lacking TP53 demonstrated a decreased response to CPUY201112 in culture, when compared to osteosarcoma cells with wild-type TP53 (PMID: 26743233).||26743233|
|TP53 loss||colon cancer||decreased response||CPUY201112||Preclinical||Actionable||In a preclinical study, colon cancer cells lacking TP53 had a decreased response to CPUY201112 in culture, when compared to colon cancer cells with wild-type TP53 (PMID: 26743233).||26743233|