Calpains are a class of intracellular cysteine proteases regulated by the second messenger, Ca 2. Several Calpain isoforms have been reported of which Calpains I and II are the most ubiquitous in mammalian cells. Calpains are believed to be important modulators of a number of physiologic and pathologic events in cells. The enzyme has a broad substrate specificity and many Calpain substrates such as the transcription factors c-Fos and c-Jun, the tumor suppressor protein p53, multiple signaling enzymes (e.g., protein kinase C, pp60 src) and the adhesion molecules integrin and E-cadherin have been implicated in the pathogenesis of different human tumors. It has also been demonstrated in cell culture studies that inhibition of Calpain triggers apoptosis in cancer cell lines. These studies suggest that Calpain is a potential new cancer target for the discovery of a new class of antitumor agents. There is however, a paucity of in vivo studies (animal studies) that validate Calpain as a viable cancer target for anticancer drug discovery. The link between in vitro Calpain inhibition and in vivo anticancer activity is under-explored due in part to the metabolic instability of most Calpain inhibitors. This constitutes a significant gap that must be addressed in order to validate Calpain as a new cancer target. The immediate goal of this proposal is to fill this gap by developing a unique series of Calpain inhibitors that are potent, selective, and metabolically stable for use as tools to validate Calpain as a new cancer target. The long-term goal is to develop Calpain inhibitors as a new class of anticancer agents.
The specific aims are to: (1) use structure-based molecular design approaches to design and synthesize metabolically stable Calpain inhibitors; (2) determine the potency and selectivity of the compounds towards Calpain inhibition versus other proteases; (3) determine the metabolic stability of the compounds; (4) determine the in vitro cytotoxicity and in vivo efficacy of the compounds; (5) determine if the inhibitory potency (Ki) of the inhibitors correlate with their in vitro cytotoxicity profiles as well as in vivo antitumor efficacy; (6) determine the mechanism(s) of Calpain inhibitor-induced cytotoxicity. The results of the proposed studies will validate Calpain as a new cancer target for anti-tumor drug discovery. Additionally, the compounds are useful biomedical tools for investigating the intracellular roles of Calpain due to their metabolic stability. The compounds are also potential anticancer agents.
| Guan, Na; Korukonda, Rajani; Hurh, Eunju et al. (2006) Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines. Int J Oncol 29:655-63 |
| Sanders, M Lee; Donkor, Isaac O (2006) A novel series of urea-based peptidomimetic calpain inhibitors. Bioorg Med Chem Lett 16:1965-8 |
