Hsp90 is a molecular chaperone, it is essential for the conformational stability and activity of many key oncogenic proteins. These proteins include not only kinases such as ErbB2, B-Raf, Alk, Flt3, EGFR, RET, KIT, PDGFR, MET, AKT, but also transcription factors, telomerase, and other proteins.
Using a specific inhibitor of Hsp90, can induce the degradation of diverse client proteins and as a consequence to achieve a parallel block of multiple signaling pathways. As a result, it leads to
cell death and inhibition of the growth of a broad range of tumors.
In this article, we will introduce an HSP90 inhibitor, NMS-E973.
NMS-E973 is a potent and selective inhibitor of HSP90. NMS-E973 binds to the ATP binding site of Hsp90α with a DC50 of <10 nM. NMS-E973 is able to cross the blood-brain barrier (BBB). Antitumor efficacy.
NMS-E973 inhibits cancer cell proliferation. It shows a widespread antiproliferative activity, with an average IC50 of 1.6 μM and 15 cell lines with an IC50 <100 nM.
Carcinoma breast DU-4475, EVSA-T, CAL-51, HCC1954, BT-474, HCC1419, HDQ-P1 cells; Leukemia MV-4-11 and MOLM-13 cells; Melanoma A-375 cells
In carcinoma breast, NMS-E973 is against DU-4475, EVSA-T, CAL-51, HCC1954, BT-474, HCC1419, HDQ-P1 cells with IC50s of 13, 16, 56, 61, 73, 76, and 89 nM, respectively. Additionally, it exhibits IC50s of 29 and 35 nM for MV-4-11, MOLM-13 cells, respectively.
In Balb/c male nude mice xenografted with the A375 tumors. NMS-E973 inhibits the growth of A375 tumors subcutaneously or intracranially implanted in mice. Both schedules result in tumor shrinkage and TGI of 74% and 89%, respectively.
Following intravenous administration (10 mg/kg) in mice. This compound exhibits moderate elimination half-lives (5.55±1.07 h) due to high plasma clearance (39.9±1.70 mL/min/kg) combined with large volumes of distribution (5.83±3.18 L/kg).
In conclusion, NMS-E973, as an Hsp90 inhibitor, has a potential for the development of tumors research.
Reference:
Gianpaolo Fogliatto, et al. Clin Cancer Res. 2013 Jul 1;19(13):3520-32.