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Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein intera...

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Detalles Bibliográficos
Autores principales: Wang, Lei, Zhang, Lixiao, Li, Li, Jiang, Jingsheng, Zheng, Zhen, Shang, Jialin, Wang, Chengxiang, Chen, Weilin, Bao, Qichao, Xu, Xiaoli, Jiang, Zhengyu, Zhang, Jian, You, Qidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750927/
https://www.ncbi.nlm.nih.gov/pubmed/31555737
http://dx.doi.org/10.1126/sciadv.aax2277
Descripción
Sumario:Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu(47), one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.