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

Xiao-Li Xu; Qi-chao Bao; Jian-Min Jia; Fang Liu; Xiao-Ke Guo; Ming-ye Zhang; Jin-lian Wei; Meng-chen Lu; Li-li Xu; Xiao-Jin Zhang; Qi-Dong You; Hao-Peng Sun

doi:10.1038/srep19004

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

Sci Rep. 2016 Jan 8:6:19004. doi: 10.1038/srep19004.

Authors

Xiao-Li Xu^{1

2}, Qi-chao Bao^{1

2}, Jian-Min Jia^{1

2}, Fang Liu^{1

2}, Xiao-Ke Guo^{1

2}, Ming-ye Zhang^{1

2}, Jin-lian Wei^{1

2}, Meng-chen Lu^{1

2}, Li-li Xu^{1

2}, Xiao-Jin Zhang^{1

2

3}, Qi-Dong You^{1

2

4}, Hao-Peng Sun^{1

2

4}

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
³ Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 210009, China.
⁴ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy*
Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Animals
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Drug Synergism
Female
Gene Expression Regulation, Neoplastic*
HSP90 Heat-Shock Proteins / antagonists & inhibitors
HSP90 Heat-Shock Proteins / genetics*
HSP90 Heat-Shock Proteins / metabolism
Humans
Imidazoles / pharmacology
MCF-7 Cells
Mice
Mice, Nude
Piperazines / pharmacology
Proteolysis
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-raf / genetics
Proto-Oncogene Proteins c-raf / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism
Resorcinols / chemical synthesis
Resorcinols / pharmacology*
Signal Transduction
Tumor Burden / drug effects
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
CPUY201112
HSP90 Heat-Shock Proteins
Imidazoles
Piperazines
Pyrimidines
Resorcinols
Tumor Suppressor Protein p53
nutlin 3
ERBB2 protein, human
Receptor, ErbB-2
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-raf