AUY922 and HSP990

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, c-Met, N-RAS, AKT, C-KIT, PDGFR, VEGFR, 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

Novartis Oncology is currently developing a novel, highly potent, non-geldanamycin derivative HSP90 inhibitor, AUY922, 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, gastric cancer, NSCL cancer, and others.

Currently, AUY922 is being investigated in Phase I and II clinical trials in both hematologic malignancies and solid tumors.

HSP990 is being investigated in Phase 1 clinical trials in solid tumors.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

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.