Abstract A213: Potent anticancer activity in vitro and in vivo by NMS‐E973, a novel synthetic inhibitor of HSP90

The molecular chaperone heat shock protein 90 (HSP90) is essential for the conformational maturation and stability of a variety of proteins, including kinases, transcription factors, telomerase, and other key proteins implicated in cancer development and progression. The simultaneous block of multiple signaling pathways that is induced by Hsp90 inhibition makes this approach potentially attractive in a broad range of cancer types.

Prototype geldanamicyn‐derivative HSP90 inhibitors have already shown efficacy in different types of tumors, but possess liabilities inherent to the class which may ultimately limit their development. Here we describe the in vitro and in vivo characterisation of NMS‐E973, representative of a novel class of non‐ansamycin Hsp90 inhibitors. NMS‐E973 binds HSP90 with picomolar affinity, as revealed by Surface Plasmon Resonance analysis, whereas selectivity screening showed no significant activity against a broad panel of kinases, as well as other ATPases. NMS‐E973, when profiled against a panel of 91 tumor cell lines of various tissue origins, showed widespread antiproliferative activity. On‐target mechanism was confirmed in multiple cell lines by observation of dose and time dependent degradation of specific oncogenes, parallel blockade of the PI3K and RAF/MEK/ERK pathways, and upregulation of HSP70, a well‐known feedback response to HSP90 inhibition. In vivo, NMS‐E973 had a favourable pharmacokinetic profile, good tolerability, selective retention in tumors, and induced tumor shrinkage in multiple human xenograft models in nude mice. In the B‐RAF ^V600E driven A375 melanoma model, for which a multi‐cycle regimen was adopted, shrinkage was observed both during the first treatment cycle, as well as after successive re‐challenge of larger, regrown tumor masses. In conclusion, NMS‐E973 is a novel, potent non‐ansamycin like inhibitor of HSP90, with efficacy and pharmacokinetic properties compatible with clinical development.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A213.