HMGB1-Directed drug discovery targeting cutaneous inflammatory dysregulation

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 2010

Fingerprint

Pathology
Drug Discovery
Drug Delivery Systems
Skin
Modulation
Molecules
Serine Proteinase Inhibitors
Toll-Like Receptors
Nicotinic Receptors
Nuclear Proteins
Biological Products
Pharmaceutical Preparations
Modulators
Toxicity
Repair
Anti-Inflammatory Agents
Tissue
Cytokines
Ligands
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry

Cite this

HMGB1-Directed drug discovery targeting cutaneous inflammatory dysregulation. / Lamore, Sarah D.; Cabello, Christopher M.; Wondrak, Georg T.

In: Current Drug Metabolism, Vol. 11, No. 3, 03.2010, p. 250-265.

Research output: Contribution to journalArticle

Lamore, Sarah D. ; Cabello, Christopher M. ; Wondrak, Georg T. / HMGB1-Directed drug discovery targeting cutaneous inflammatory dysregulation. In: Current Drug Metabolism. 2010 ; Vol. 11, No. 3. pp. 250-265.
@article{3866db5510d041aeaccdb1eab905cad5,
title = "HMGB1-Directed drug discovery targeting cutaneous inflammatory dysregulation",
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 = "Cutaneous pharmacotherapy, Cytokine, Drug discovery, HMGB1, Inflammation, Molecular target, RAGE, Skin",
author = "Lamore, {Sarah D.} and Cabello, {Christopher M.} and Wondrak, {Georg T}",
year = "2010",
month = "3",
doi = "10.2174/138920010791196337",
language = "English (US)",
volume = "11",
pages = "250--265",
journal = "Current Drug Metabolism",
issn = "1389-2002",
publisher = "Bentham Science Publishers B.V.",
number = "3",

}

TY - JOUR

T1 - HMGB1-Directed drug discovery targeting cutaneous inflammatory dysregulation

AU - Lamore, Sarah D.

AU - Cabello, Christopher M.

AU - Wondrak, Georg T

PY - 2010/3

Y1 - 2010/3

N2 - 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.

AB - 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.

KW - Cutaneous pharmacotherapy

KW - Cytokine

KW - Drug discovery

KW - HMGB1

KW - Inflammation

KW - Molecular target

KW - RAGE

KW - Skin

UR - http://www.scopus.com/inward/record.url?scp=77951703961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951703961&partnerID=8YFLogxK

U2 - 10.2174/138920010791196337

DO - 10.2174/138920010791196337

M3 - Article

C2 - 20406187

AN - SCOPUS:77951703961

VL - 11

SP - 250

EP - 265

JO - Current Drug Metabolism

JF - Current Drug Metabolism

SN - 1389-2002

IS - 3

ER -