Novel Small Molecule Therapeutic for Vitiligo

PROJECT SUMMARY/ABSTRACT Vitiligo is characterized by the patchy loss of skin pigmentation that can adversely affect a person’s quality of life and sense of well-being. Despite the prevalence of vitiligo [over 2 million U.S. citizens are affected by vitiligo and the global cases range from 0.5% to 2% of the population], there is only one FDA-approved therapeutic for vitiligo; a topical formulation of the Janus kinase (JAK)-inhibitor sold under the trade name Opzelura. Significant shortcomings of Opzelura include: the limited response rate and the high cost. Thus, there is a critical need for the development of novel therapeutics for vitiligo. The long-term research goal of this project is to discover and develop safe and cost effective small organic compounds that can be used as therapeutics for vitiligo. Investigations into the autoimmune mechanisms of vitiligo have revealed: (i) high levels of expression of the cytokine CXCL10 at active sites of vitiligo in murine and human tissue; (ii) that inhibition of interferon-gamma (IFN-γ) signaling, which induces CXCL10 expression, is protective from vitiligo in a murine model; and (iii) that neutralization of CXCL10 can induce reversal of the disease in a murine model. These observations have led to the conjecture that reagents which inhibit IFN-γ induced CXCL10 expression by keratinocytes, the main source of CXCL10, could be developed into therapeutics for vitiligo. The research team has identified a family of highly potent and specific inhibitors of glycogen synthase kinase-3 (GSK-3). The team recently discovered that COB-187, the lead compound within this family, inhibits IFN-γ induced CXCL10 expression by human keratinocytes. These observations have led us to the following central hypothesis: COB-187 is efficacious in vitiligo. To investigate this hypothesis, the following aims will be completed: (i) to determine the ability of COB-187 to attenuate IFN-γ induced cytokine expression by human keratinocytes; and (ii) to determine the mechanism by which COB-187 inhibits IFN-γ induced CXCL10 expression by keratinocytes. The family of compounds exemplified by COB-187 have the potential to become therapeutics for vitiligo. The proposed work will provide a strong scientific foundation for the development of such therapeutics. Thus, successful completion of these studies will have a positive impact on the large number of people who suffer from vitiligo.