MedKoo product information:

  HSP-990

Description of HSP-990: HSP990 is an orally bioavailable inhibitor of human heat-shock protein 90 (Hsp90) with potential antineoplastic activity.  Hsp990 binds to and inhibits the activity of Hsp90, which may result in the proteasomal degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation. Hsp90, upregulated in a variety of tumor cells, is a molecular chaperone that plays a key role in the conformational maturation, stability and function of oncogenic signaling proteins, such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutated p53, as well as many other molecules that are important in cell cycle regulation and/or immune responses. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Novartis.

HSP990 - Activities In Vitro and In Vivo. Scientists from Novartis reported the following results: In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. (source: Mol Cancer Ther; 11(3); 730-9.)

Preclinical activity of  NVP-HSP990 against multiple myeloma cells. NVP-HSP990 exerted profound activity against MM cells, with a molecular mode of action conforming well with its role as HSP90 inhibitor. Enhanced activity was most obvious in combination with melphalan. Combination with a phosphatidylinositol-3-kinase (PI3-kinase)/mammalian target of rapamycin (mTOR) inhibitor, rendered the HSP90 blockade-mediated stress response ineffective and considerably increased the anti-MM toxicity (source: Anticancer Res. 2012 Feb;32(2):453-62.).

Research publications related to HSP-990:

1: Lamottke B, Kaiser M, Mieth M, Heider U, Gao Z, Nikolova Z, Jensen MR, Sterz J, von Metzler I, Sezer O. The novel, orally bioavailable HSP90 inhibitor NVP-HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases. Eur J Haematol. 2012 Feb 6. doi: 10.1111/j.1600-0609.2012.01764.x. [Epub ahead of print] PubMed PMID: 22309072.

2: Stühmer T, Iskandarov K, Gao Z, Bumm T, Grella E, Jensen MR, Einsele H, Chatterjee M, Bargou RC. Preclinical activity of the novel orally bioavailable HSP90 inhibitor NVP-HSP990 against multiple myeloma cells. Anticancer Res. 2012 Feb;32(2):453-62. PubMed PMID: 22287732.

3: Menezes DL, Taverna P, Jensen MR, Abrams T, Stuart D, Yu GK, Duhl D, Machajewski T, Sellers WR, Pryer NK, Gao Z. The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor Activities In Vitro and In Vivo. Mol Cancer Ther. 2012 Mar;11(3):730-9. Epub 2012 Jan 12. PubMed PMID: 22246440.

4: Khong T, Spencer A. Targeting HSP 90 induces apoptosis and inhibits critical survival and proliferation pathways in multiple myeloma. Mol Cancer Ther. 2011 Oct;10(10):1909-17. Epub 2011 Aug 22. PubMed PMID: 21859842.

5: Jackrel ME, Shorter J. Shock and awe: unleashing the heat shock response to treat Huntington disease. J Clin Invest. 2011 Aug;121(8):2972-5. doi: 10.1172/JCI59190. Epub 2011 Jul 25. PubMed PMID: 21785212; PubMed Central PMCID: PMC3148752.

Patents related to HSP-990

1. Solid oral formulations of a pyridopyrimidinone By Verma, Daya; Teng, Yue; Singh, Rajinder; Thompson, Dan From PCT Int. Appl. (2010), WO 2010088336 A1 20100805.

2. Hsp90 inhibitors for therapeutic treatment of cancer and other disorders By Jensen, Michael Rugaard; Quadt, Cornelia From PCT Int. Appl. (2010), WO 2010060940 A2 20100603.

3. Hsp90 inhibitor combinations with an mTOR inhibitor for treatment of proliferative diseases By Jensen, Michael Rugaard From PCT Int. Appl. (2010), WO 2010060937 A2 20100603.

4. Pharmaceutical combination of Hsp90 and herceptin inhibitors for treating proliferative disorders By Garcia-Echeverria, Carlos; Jensen, Michael From PCT Int. Appl. (2010), WO 2010060939 A2 20100603.

5. Oxime derivatives as HSP90 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of diseases By Chen, Young K.; Co, Erick Wang; Guntupalli, Prasuna; Lawson, John David; Notz, Wolfgang Reinhard Ludwig; Stafford, Jeffrey A.; Ton-Nu, Huong-Thu From PCT Int. Appl. (2009), WO 2009097578 A1 20090806.

6. Preparation of 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-ones as inhibitors of HSP90 for treating cellular proliferative, viral, autoimmune, cardiovascular, and central nervous system diseases By Machajewski, Timothy D.; Shafer, Cynthia M.; McBride, Christopher; Antonios-McCrea, William; Doughan, Brandon M.; Levine, Barry H.; Xia, Yi; McKenna, Maureen; Wang, X. Michael; Mendenhall, Kris; et al From PCT Int. Appl. (2007), WO 2007041362 A1 20070412.