NMS-E973 is a potent and selective inhibitor of heat shock protein 90 (Hsp90) with DC50 value of < 10nM [1].
Since Hsp90 plays an important role in the conformational maturation, stability and function of some oncogenic proteins, the inhibitors of Hsp90 are developed as therapeutic for cancers. NMS-E973 is a selective inhibitor of Hsp90. It binds to Hsp90α within the ATP binding site with DC50 value of < 10nM. Besides that, NMS-E973 shows no effect on a panel of 52 various protein kinases such as ABL, ACK1, AKT1 and Alk. The IC50 value of it for Hsc70 is > 10μM. NMS-E973 exerts antiproliferation effects on A2780 tumor cell line and BT-474 breast cancer cell line with IC50 values of 69nM and 110nM, respectively. When treated with mice bearing A2780 xenografts, the intravenous administration of NMS-E973 significantly inhibits tumor growth with TGI value of 53% at dose of 30mg/kg. Moreover, NMS-E973 also displays antitumor activity in tumors resistant to kinase inhibitors such as vemurafenib [1, 2].
References:
[1] Brasca M G, Mantegani S, Amboldi N, et al. Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90). Bioorganic & medicinal chemistry, 2013, 21(22): 7047-7063.
[2] Fogliatto G, Gianellini L, Brasca M G, et al. NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases. Clinical Cancer Research, 2013, 19(13): 3520-3532.