The biological function against obesity of heat shock protein Hsp72 in adipose tissue has remained unclear. Our findings demonstrated that the expression levels of Hsp72 increased during the triglyceride (TG) accumulation process both in adipose tissue and 3T3-L1 cells. A significant decrease in adipogenic gene expression and TG levels was observed upon Hsp72 knockdown in 3T3-L1 cells, suggesting that Hsp72 promoted adipogenic differentiation and lipid synthesis processes. Encouraged by these findings, we further confirmed the allosteric Hsp72 inhibitors YK5 and MKT-077 also exhibited inhibition of both these processes. Further evaluation revealed that Hsp72 played a key role in interacting with numerous novel metabolic and cytomorphologic-related client proteins, thereby mediating the adipogenesis and lipogenesis process. Hsp72 inhibitors had the potential to disrupt these interactions, leading to the downregulation of adipogenic and lipogenic gene expression, as well as the suppression of TG accumulation. These findings suggested that inhibiting Hsp72 to disrupt adipogenic differentiation and lipid synthesis in adipocytes may be a promising anti-obesity strategy.

2013-12-01·Chemistry & Biology

Identification of an Allosteric Pocket on Human Hsp70 Reveals a Mode of Inhibition of This Therapeutically Important Protein

Article

作者: Wong, Michael J H ; Maharaj, Ronnie ; Patel, Maulik R ; Young, Jason C ; Kang, Yanlong ; Taldone, Tony ; Yan, Pengrong ; Patel, Yogita ; Erdjument-Bromage, Hediye ; Chiosis, Gabriela ; Patel, Hardik J ; Patel, Pallav D ; Yang, Chenghua ; Talele, Tanaji T ; Baaklini, Imad ; Gozman, Alexander ; Rodina, Anna ; Chirico, William

Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70.

100 项与 YK-5 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床2期	美国	Memorial Sloan Kettering Cancer Center	-
肿瘤	药物发现	美国	The Leukemia & Lymphoma Society, Inc.	-
肿瘤	药物发现	美国	Weill Medical College of Cornell University	-