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Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata
J. Tsai, S. Gori, J. Alt, S. Tiwari, J. Iyer, R. Talwar, D. Hinsu, K. Ahirwar, S. Mohanty, C. Khunt, B. Sutariya, K. Jani, V. Venkatasubbaiah, A. Patel, J. Meghapara, K. Joshi, R. Sahu, V. Rana, P. Nigade, RS. Talluri, KVSN. Murty, K. Joshi, V....
Status neindexováno Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články
NLK
Directory of Open Access Journals
od 2022
PubMed Central
od 2022
Oxford Journals Open Access Collection
od 2022-03-01
ROAD: Directory of Open Access Scholarly Resources
od 2022
- Publikační typ
- časopisecké články MeSH
Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+ T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.
Clinical Pharmacology Sun Pharma Advanced Research Company Mahakali Mumbai 400093 India
Department of Cell Biology Johns Hopkins University Baltimore MD 21205 USA
Department of Dermatology Johns Hopkins University School of Medicine Baltimore MD 21205 USA
Department of Medicine Johns Hopkins University School of Medicine Baltimore MD 21205 USA
Department of Neurology Johns Hopkins University School of Medicine Baltimore MD 21205 USA
Department of Neuroscience Johns Hopkins University Baltimore MD 21205 USA
Department of Oncology Johns Hopkins University School of Medicine Baltimore MD 21205 USA
Drug Metabolism and Pharmacokinetics Sun Pharma Advanced Research Company Savli 391770 India
In Vitro Biology Sun Pharma Advanced Research Company Savli 391770 India
Johns Hopkins Drug Discovery Johns Hopkins University School of Medicine Baltimore MD 21205 USA
Medicinal Chemistry Sun Pharma Advanced Research Company Savli 391770 India
Preclinical Pharmacology Sun Pharma Advanced Research Company Savli 391770 India
Translational Development Sun Pharma Advanced Research Company Savli 391770 India
Citace poskytuje Crossref.org
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- $a Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+ T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.
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