生物活性

• 描述Heat shock protein 90 (Hsp90) is a molecular chaperone protein that stabilizes client oncogenic proteins in breast cancer cells. PU-H71 is a novel Hsp90 inhibitor with an IC50 value of 51nM. The treatment with PU-H71 at a dosage of 1µM resulted in significant cell death in triple-negative breast cancer (TNBC) cell lines MDA-MB-468 (80%), MDA-MB-231 (65%), and HCC-1806 (80%). The inhibition of Hsp90 by PU-H71 (10–1000nM) induced a concentration-dependent inactivation or degradation of tumor driving molecules, including epidermal growth factor receptor, insulin-like growth factor receptor, HER3, and c-Kit. PU-H71 (10–1000nM) also downregulated the proteins related to G₂-M progression, such as cyclin-dependent kinase 1 and checkpoint kinase 1. The treatment of MDA-MB-468 cells with 0.25, 0.5, and 1μM PU-H71 for 24 h increased the percentage of cells in G₂-M phase to 30%, 44%, and 69%, respectively. PU-H71 at 250–1000nM induced apoptosis in TNBC cells by inactivating and downregulating Bcl-xL and Akt. The treatment of MDA-MB-231 cells with 0.5 and 1μM PU-H71 for 24 h reduced the NF-κB activity by 84% and 90%, respectively. In the MDA-MB-231 xenograft mouse model, PU-H71 (75 mg/kg on an alternate day schedule) completely inhibited tumor growth after 37 days of treatment. In the fast growing HCC-1806 tumors, six doses of PU-H71 (75 mg/kg on an alternate day schedule) over a 12 days resulted in an 87% regression in tumor volume.
• 作用机制PU-H71 is a potent inhibitor of Hsp90 both in vitro and in vivo. When Hsp90 is inactivated, many TNBC oncoproteins that form a complex with PU-H71-bound Hsp90 become destabilized and subsequently degraded.