HMGB1-Directed drug discovery targeting cutaneous inflammatory dysregulation

Sarah D. Lamore, Christopher M. Cabello, Georg T. Wondrak

Research output: Contribution to journalReview article

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)250-265
Number of pages16
JournalCurrent Drug Metabolism
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2010

    Fingerprint

Keywords

  • Cutaneous pharmacotherapy
  • Cytokine
  • Drug discovery
  • HMGB1
  • Inflammation
  • Molecular target
  • RAGE
  • Skin

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry

Cite this