DDO-5936
目录号 : GC62305DDO-5936 是一种有效且特异的 Hsp90-Cdc37 PPI 抑制剂。DDO-5936 可用于大肠癌的研究。
Cas No.:2355377-13-6
Sample solution is provided at 25 µL, 10mM.
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DDO-5936 is a potent and specific Hsp90-Cdc37 PPI inhibitor. DDO-5936 can be used for the research of colorectal cancer[1].
DDO-5936 is a Hsp90-Cdc37 PPI inhibitor with potency and specificity through binding to a critical site on Hsp90 involving Glu47[1].
DDO-5936 (0~80 mg/kg; p.o.) shows effect at the high dose group[1].DDO-5936 is well tolerated for the absence of serious weight loss. DDO-5936 high dose groups show that tumor cells in the xenografts decreased significantly. DDO-5936 shows limited oral efficiency[1].
[1]. Wang L, et al. Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer. J Med Chem. 2020;63(3):1281-1297.
Cas No. | 2355377-13-6 | SDF | |
分子式 | C25H29N5O4S | 分子量 | 495.59 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.0178 mL | 10.089 mL | 20.178 mL |
5 mM | 0.4036 mL | 2.0178 mL | 4.0356 mL |
10 mM | 0.2018 mL | 1.0089 mL | 2.0178 mL |
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Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer
Sci Adv 2019 Sep 18;5(9):eaax2277.PMID:31555737DOI:10.1126/sciadv.aax2277.
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 Glu47, 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.
Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer
J Med Chem 2020 Feb 13;63(3):1281-1297.PMID:31935086DOI:10.1021/acs.jmedchem.9b01659.
Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 μM) and cellular inhibitory activity (IC50 = 1.73 μM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.