Hsp90-Cdc37-IN-3

Hsp90-Cdc37-IN-3 (Compound 9) is a novel celastrol−imidazole derivative with anticancer activity. Hsp90-Cdc37-IN-3 inhibits Hsp90−Cdc37 by covalent-binding, and induces apoptosis[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> HSP

Signaling Pathways >> Cell Cycle/DNA Damage >> HSP

Hsp90-Cdc37

Hsp90-Cdc37-IN-3 (Compound 9) (24 h) shows broad-spectrum antitumor potential with IC50 values of 0.54, 0.59, 0.57, and 0.57 µM against A549, HTC116, U2OS, and MDA-MB231 cells, respectively[1]. Hsp90-Cdc37-IN-3 (0-5 µM, 12 h) inhibits Hsp90−Cdc37 and influences the function of apoptosis-related proteins by covalently combining with both Hsp90 and Cdc37[1]. Hsp90-Cdc37-IN-3 (0-0.8 µM, 48 h) induces apoptosis significantly in A549 cells[1]. Hsp90-Cdc37-IN-3 (0-0.4 µM, 24 h) arrests the cell cycle in the G0/G1 phase in a dose-dependent manner[1]. Western Blot Analysis[1] Cell Line: A549 Concentration: 1.25, 2.5, and 5 µM Incubation Time: 12 h Result: Downregulated the levels of Hsp90−Cdc37 clients (p-Akt and Cdk4) in a dose-dependent manner, and the levels of apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3, and cleaved PARP) were significantly regulated. Apoptosis Analysis[1] Cell Line: A549 Concentration: 0.2, 0.4, and 0.8 μM Incubation Time: 48 h Result: Induced apoptosis significantly. Cell Cycle Analysis[1] Cell Line: A549 Concentration: 0.1, 0.2, and 0.4 μM Incubation Time: 24 h Result: Arrested the cell cycle in the G0/G1 phase in a dose-dependent manner.

Hsp90-Cdc37-IN-3 (Compound 9) (0-1 mg/kg; i.p.; once a day, 21 days) shows strong antitumor activity with no significant toxicity[1]. Animal Model: Female BALB/c nude mice at 6 weeks old[1]. Dosage: 0.5 mg/kg or 1 mg/kg. Mice were inoculated subcutaneously with A549 cells (1*107 in 100 μL of PBS for each mouse). Administration: Intraperitoneal injection, once a day, 21 days Result: Decreased tumor weight and enhanced TIR without show toxicity.

[1]. Na Li, et al. Discovery of Novel Celastrol-Imidazole Derivatives with Anticancer Activity In Vitro and In Vivo. J Med Chem. 2022 Mar 24;65(6):4578-4589.