HMGB1-Directed Drug Discovery Targeting Cutaneous Inflammatory Dysregulation

Author(s): Sarah D. Lamore, Christopher M. Cabello, Georg T. Wondrak

Journal Name: Current Drug Metabolism

Volume 11 , Issue 3 , 2010


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Abstract:

Extracellular cytokine function of the non-histone nuclear protein high-mobility group box 1 (HMGB1) has recently been recognized as an important drug target for novel anti-inflammatory therapeutics. Accumulating evidence supports the mechanistic involvement of the alarmin HMGB1 in skin response to microbial infection and ultraviolet-induced solar damage. Moreover, HMGB1 modulation of inflammatory signaling and tissue remodeling is now emerging as a causative factor in wound repair, autoimmune dysregulation, and skin carcinogenesis, representing cutaneous pathologies that affect large patient populations with unmet therapeutic needs. Recent structure-based drug discovery efforts have aimed at increasing the number of small molecule- and biologics-based prototype therapeutics targeting HMGB1. Small molecule drugs that may provide therapeutic benefit through HMGB1-directed mechanisms involve HMGB1 inhibitory ligands, Toll-like receptor antagonists, RAGE antagonists, α7 nicotinic acetylcholine receptor agonists, G2A antagonists, serine protease inhibitors, and α-dicarbonyl-based soft electrophiles. Using some of these agents, pharmacological modulation of HMGB1-associated cutaneous pathology has been achieved with an acceptable toxicity profile, and preclinical proof-of-concept experimentation has demonstrated feasibility of developing HMGB1-modulators into novel systemic and topical therapeutics that target cutaneous inflammatory dysregulation.

Keywords: HMGB1, RAGE, cytokine, inflammation, skin, drug discovery, molecular target, cutaneous pharmacotherapy

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Article Details

VOLUME: 11
ISSUE: 3
Year: 2010
Page: [250 - 265]
Pages: 16
DOI: 10.2174/138920010791196337
Price: $65

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