Onalespib (AT13387) is a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Onalespib selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins.

HSP90 (AT13387):18 nM

当间歇给药时,AT13387耐受剂量高达70 mg/kg每周两次或90 mg/kg每周一次.在两种给药方案中,NCI-H1975的肿瘤生长抑制是相似的.

AT13387是来自多种不同肿瘤类型的许多不同细胞系（例如MES-SA细胞系）的增殖和存活的有效抑制剂。在一组30个肿瘤细胞系中,AT13387有效抑制细胞增殖,GI50值在13-260 nM范围内。 AT13387抑制非致瘤性人前列腺上皮细胞系PNT2的增殖,GI50值为480 nM。

HSP90 competition isothermal calorimetry: Kd values for AT13387 binding to HSP90 are determined with a competition Isothermal Calorimetry (ITC) format. ITC experiments are performed on a Micro Cal VP-ITC at 25 °C in a buffer comprising 25 mM Tris, 100 mM NaCl, 1 mM MgCl2 and 1 mM Tris(2-carboxy- ethyl)phosphine at pH 7.4 in order to maintain the higher affinit

The human cell lines including A375, 22RV1, T474, DU1 45, LNCa P, MCF-7, DA-MB-468 are seeded into 96-well plates before the addition of AT13387 in 0.1% (v/v) DMSO. GI50 are determined using a 10-point dose response curve for three cell doubling times. After AT13387 incubation 10% (v/v), Alamar blueis added, and cells are incubated for a further 4 hours. Fluorescence is read.(Only for Reference)