HSP70 Inhibitor Program

Due to their enhanced stress environment cancer cells are particularly dependent upon activity of chaperone proteins, in particular HSP70, to maintain proper folding of cellular proteins. In support of this observation, HSP70 is constitutively expressed at elevated levels in most cancer calls, and silencing or inhibiting HSP70 is selectively cytotoxic to tumor cells. These observations have generated a great deal of interest in HSP70 as a target for new oncology therapeutics. However, identifying selective HSP70 inhibitors has proven difficult as most attempts have targeted the nucleotide binding domain, which is conserved amongst other, essential, HSP family members and thus accompanied by normal cell toxicity.Due to their enhanced stress environment cancer cells are particularly dependent upon activity of chaperone proteins, in particular HSP70, to maintain proper folding of cellular proteins. In support of this observation, HSP70 is constitutively expressed at elevated levels in most cancer calls, and silencing or inhibiting HSP70 is selectively cytotoxic to tumor cells. These observations have generated a great deal of interest in HSP70 as a target for new oncology therapeutics. However, identifying selective HSP70 inhibitors has proven difficult as most attempts have targeted the nucleotide binding domain, which is conserved amongst other, essential, HSP family members and thus accompanied by normal cell toxicity.

1. Targeting of unique site: Drs. Murphy, George and Leu used a structure-activity approach and biophysical methods to characterize a class of inhibitors that bind to a unique allosteric site, independent of the nucleotide binding domain, within the C-terminal Substrate binding domain of HSP70. X-ray crystallography, isothermal titration calorimetry and mutagenesis studies revealed that these inhibitors bind to a pocked formed within the non-ATP-bound protein state and thereby alter the protein’s conformation resulting in reduced interaction with client proteins and impairment of proteostasis.
   
   
2. Hit to lead optimization: Compound optimization, by testing derivatives of hit compound, identified key chemical features required for selective cytotoxicity in cancer cells.
   
   
3. Lead compound series efficacy: Lead series compounds have an IC50 of ~0.1-1.5 µM in several cancer cell lines, and an IC50 of more than 100 µM in non-cancerous cells and protect Eµ-myc mice from lymphoma (p < 0.00001).

The inventors are currently conducting additional experiments to further optimize the lead candidate, and plan to initiate PD/PK studies.

Issued and pending patent applications cover compositions and methods of use. US9,296,687; US13/051511.

We are actively seeking licensing and/or developmental collaborations to help accelerate the preclinical research as well as identify additional compounds that may prove to be therapeutically useful.

1. Leu, et al ACS Chem Biol. 2014;9(11):2508-2516. PMID: 25148104
   
   
2. Balaburski et al Mol Cancer Res. 2013;11:219-229. PMID: 23303345
   
   
3. Leu et al Mol Cell. 2009;36(1): 15-27. PMID: 19818706
   
   
4. Zhang et al PLoS One. 2014 24;9(7):e103518. PMID: 25058147