Isoprenylcysteine (IPC) analogs, such as N-acetyl-S-farnesyl-L-cysteine (AFC) modulate heterotrimeric G- protein and Ras-related signaling pathways, representing a potentially novel class of topical anti- inflammatory compounds. Using mouse models for acute dermal inflammation and allergic contact hypersensitivity, preliminary results demonstrate that AFC is an effective topical anti-inflammatory in vivo, comparable in activity to glucocorticoids and standard non-steroidal anti-inflammatory drugs (NSAIDs), but lower in potency. Moreover, results indicate that AFC has a superior safety profile in large part because it appears to be restricted to the site of topical application, while this is clearly not the case for glucocorticoids such as hydrocortisone and dexamethasone (Dex), as well as NSAIDs such as indomethacin. The proposed Phase I research plan will test the hypothesis that IPC analogs in general and AFC in particular are safe and efficacious for use as topical anti-inflammatories, by establishing the basis for its local restriction and showing that it does not have adverse side effects on skin such as thinning and inhibition of wound healing that are known consequences of chronic application of Dex. By evaluating AFC's activity in mouse models for inflammatory diseases mediated by adaptive immunity, additional evidence will be gathered to demonstrate its potential value as an alternative to steroids as well as other anti-inflammatory therapeutics. Combinations of in vitro biochemical and cell-based assays will be used to validate a screen to predict the in vivo activity of new IPC analogs, enabling quantitative structure-activity relationship studies. This will lead in Phase II to a program to identify and develop novel pharmaceutical leads for the treatment of inflammatory skin diseases such as atopic dermatitis and psoriasis. ? ? ?
