STA-1474

STA-1474 is an orally active and highly selective HSP90 inhibitor, as well as a phosphate prodrug of the HSP90 inhibitor STA-9090 (HY-15205). STA-1474 disrupts the chaperone function of HSP90 and promotes the degradation of client proteins. STA-1474 inhibits the phosphorylation of Met, Akt and STAT3, thereby blocking related signaling pathways. STA-1474 induces apoptosis and inhibits proliferation of osteosarcoma cells, and triggers the up-regulation of HSP70 and HSP90. STA-1474 induces tumor regression and caspase-3 activation in mouse osteosarcoma xenograft models. STA-1474 can be used in the research of osteosarcoma^[1]. In Vitro:STA-1474 (0.001-1 μM; 1-7 days) potently inhibits the proliferation of D17, OSA2, OSA8 and MG63 osteosarcoma cell lines, with IC₅₀ values ranging from 0.011 μM to 0.043 μM, and exhibits selectivity for OSA cells relative to normal canine osteoblasts (IC₅₀ = 0.072 μM)^[1].
STA-1474 (0.1 μM; 24-48 h, followed by drug-free incubation for 2-6 h) mediates time-dependent and reversible downregulation of p-STAT3 in MG63 and D17 osteosarcoma cell lines, which confirms that this effect directly results from HSP90 inhibition rather than non-specific toxicity^[1].
STA-1474 (0.01-1 μM; 24-48 h) induces dose-dependent apoptosis in OSA8 and MG63 osteosarcoma cell lines, but does not affect apoptosis in normal canine osteoblasts; it activates caspase 3/7 in a dose-dependent manner in D17 and OSA8 osteosarcoma cell lines, and induces dose-dependent PARP cleavage in D17, OSA2, OSA8 and MG63 osteosarcoma cell lines; it downregulates HSP90 client proteins (p-Met, total Met, p-Akt, total Akt, p-STAT3), and induces upregulation of stress response proteins HSP70 and HSP90^[1]. In Vivo:STA-1474 (60 mg/kg; intravenous injection; three times per week for 2 weeks) exhibits potent in vivo anti-osteosarcoma activity, and induces apoptosis and downregulation of client proteins^[1].