Acne is a multifactorial disease affecting ~50 million people in the US. Three main factors contribute to the pathogenesis of acne;1) P. acnes growth 2) P. acnes-induced inflammation and 3) overproduction of sebum, all targets for therapeutic intervention. Treatments, such as antibiotics and benzylperoxide (BPO) are directed at the bacterium P. acnes and retinoids target sebum control. Several antimicrobial and retinoids also possess anti-inflammatory activity. However, to date a treatment directed at all three components of acne has not been identified. Signum's isoprenylcysteine (IPC) analogs represent a novel class of topical therapeutics that potentially targets all three contributors of acne pathology. Our preliminary results demonstrate IPC analogs inhibit P. acnes growth. In addition, when topically applied, using an in vivo irritant-dermatitis inflammatory model, our results demonstrate IPC analogs have strong anti-inflammatory activity inhibiting neutrophil infiltration, edema and erythema of the skin. Preliminary results support a mechanism involving the reduction in keratinocyte inflammatory mediator production. We have extended these observations to in vitro and in vivo P. acnes-induced inflammation models, demonstrating IPC inhibition of several pro-inflammatory cytokines. Lastly, IPC analogs have also been shown to modulate GPCR signaling, suggesting a potential role in regulating sebum control through inhibition of the GPCR melanocortin 5 receptor (MC5R) (critical for sebaceous gland lipogenesis). Based on our previous work, we hypothesize by screening our library of IPC compounds we will be able to identify IPC chemotypes with plieotropic effects to be developed as a novel therapeutic for acne. Structure-activity relationship of these results will lead to proof of principle by identifying, designing and testing candidate compound(s) having the highest combined potency towards each pathological factor, which will be subsequently developed in a Phase II application.
Acne is the most common disorder of the human skin and affects up to 80% of individuals in their lives. Three main factors contributing to the pathogenesis of acne are 1) P. acnes growth 2) P. acnes-induced inflammation and 3) overproduction of sebum all of which are potential targets for therapeutic intervention. To date a treatment directed at all three components of acne has not been identified. Successful development of this novel class of topical therapeutics will be the first that potentially target all three contributors of acne pathology.
