STA-9090 is a second-generation Hsp90 inhibitor in clinical development by Synta
Pharmaceuticals for the intravenous treatment of hematological and solid
malignancies. It is a
resorcinol-containing
triazole compound, with a novel chemical structure that is unrelated to the
geldanamycin class of Hsp90 inhibitors.
STA-9090 binds to the
ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing degradation of multiple oncogenic Hsp90 client
proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2, c-Met, and
Wilms' tumor 1.
STA-9090, at low nanomolar concentrations, potently arrested cell proliferation and induced apoptosis in a wide variety of human
cancer cell lines, including many
receptor tyrosine kinase inhibitor- and
tanespimycin-resistant cell lines. Moreover, administration of
STA-9090 led to significant
tumor shrinkage in several
tumor xenograft models in mice and appeared to be less toxic. Furthermore
STA-9090 demonstrated better
tumor penetration compared with
tanespimycin. In initial phase I clinical trials,
STA-9090 was well tolerated and has demonstrated activity. The further development of this agent, and the other Hsp90 inhibitors, may be dependent on the
tumor type and the primary oncogenic driving forces.