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AUY922

Blocking tumor growth by inhibiting Heat Shock Protein 90 (HSP90)

Heat Shock Proteins (HSP) are molecular chaperones that assist in the structural formation and folding of a wide variety of oncogenic client proteins such as HER2, ER, N-RAS, AKT, C-KIT, PDGFR, and B-RAF.^1,2-4 The mutated forms of such proteins are generally more dependent on the chaperoning function of HSP90. If these proteins are misfolded, they become subject to ubiquitination and proteasomal degradation. HSP90 is the most abundant molecular chaperone and is essential for cell survival, proliferation and apoptosis.^3,5

HSP90 is an important target for cancer chemotherapeutics because tumor cells, especially those with mutations, exist in a stressful environment and depend on HSP90 to grow and survive. If HSP90 is inhibited, the regulation of tumor cell survival, proliferation and apoptosis are significantly affected.¹ For this reason, HSP90 inhibitors are considered to be agents with strong therapeutic potential in a wide variety of tumor types. In tumors, HSP90 exists in an activated state (complex), with higher affinity for HSP90 inhibitors, compared with normal cells, which provides opportunity for a therapeutic window.²

AUY922 is a novel, highly potent HSP90 inhibitor that competitively inhibits the ATPase activity of HSP90. Both in vitro and in vivo studies indicate that AUY922 has significant antitumor activity in a wide range of mutated and wild-type cancer cell lines, primary tumor cells and animal models of cancer, including breast cancer, multiple myeloma and others.

Currently, the first-in-man Phase I/II study with AUY922 in patients with advanced solid tumors is ongoing.

1. Drysdale MJ, Brough PA, Massey A, Jensen MR, Schoepfer J. Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Devel.2006;9:483-495.
2. Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature.2003;425:407-410.
3. Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med. 2003;228:111-133.
4. Jakob U, Buchner J. Assisting spontaneity: the role of Hsp90 and small Hsps as molecular chaperones. Trends Biochem Sci. 1994;19:205-211.
5. Brough PA, Aherne W, Barril X, et al. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem. 2008;51:196-218