Abstract #4685: Identification of a potent and specific inhibitor of Hsp90 showing in vivo efficacy.

The molecular chaperone heat shock protein 90 (Hsp90)is essential for the conformational maturation and stabilityof a variety of proteins, including kinases, transcription factors, telomerase, and other key components implicated in cancer development and progression. The simultaneous block of multiple signaling pathways that is incurred by Hsp90 inhibition makes this approach potentially attractive in a broad range of cancer types, and opens up the possibility that tumor evasion from the effects of such inhibitors will be less frequent than for agents which target single components of transduction pathways or cell division machinery. Here we describe characterisation of the biochemical, cellular, and in vivo antitumor activity of NMS-E973, a representative compound of a novel class of non-ansamycin Hsp90 inhibitors. NMS-E973 is a selective low nM inhibitor of HSP90\#945;, with no significant activity against a broad panel of kinases, as well as other ATPases. NMS-E973 was found to possess widespread antiproliferative activity when profiled against an extended panel of tumor cell lines of various tissue origins, and an HSP90 dependent mechanism was confirmed by the observation in treated cells of dose and time dependent degradation of multiple client proteins, including Her2, Akt, phosphoAKT, Cdk6, and phosphoERK, together with upregulation of HSP70, a well-known feedback response to HSP90 inhibition. In vivo, NMS-E973 has a favorable pharmacokinetic and toxicity profile, compatible with daily dosing, and effectively inhibits growth in nude mice of a human ovarian cancer xenograft model. As with the in vitro findings described above, tumor growth inhibition in vivo is concomitant with modulation of molecular markers of HSP90 inhibition.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4685.