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Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata
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SYSNO ASEP 0568134 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata Author(s) Tsai, J. (US)
Gori, S. (US)
Alt, J. (US)
Tiwari, S. (IN)
Iyer, J. (IN)
Talwar, R. (IN)
Hinsu, D. (IN)
Ahirwar, K. (IN)
Mohanty, S. (IN)
Khunt, C. (IN)
Sutariya, B. (US)
Jani, K. (IN)
Venkatasubbaiah, V. (IN)
Patel, A. (IN)
Meghapara, J. (IN)
Joshi, K. (IN)
Sahu, R. (IN)
Rana, V. (IN)
Nigade, P. (IN)
Talluri, R. S. (IN)
Murty, K. V. S. N. (IN)
Joshi, K. (IN)
Ramanathan, V. (IN)
Li, A. (US)
Islam, N. (US)
Šnajdr, Ivan (UOCHB-X) ORCID
Majer, Pavel (UOCHB-X)
Rais, R. (US)
Slusher, B. S. (US)
Garza, L. A. (US)Article number pgac297 Source Title PNAS Nexus
Roč. 2, č. 1 (2023)Number of pages 12 s. Language eng - English Country GB - United Kingdom Keywords alopecia areata ; hair growth ; topical ; itaconate ; prodrug ; inflammation ; immunosuppression ; cytokine ; interleukin ; interferon ; double-stranded RNA ; polyinosinic–polycytidylic acid ; hair cycle ; anagen ; telogen ; keratinocyte ; stability ; pharmacokinetics ; cytotoxicity OECD category Medicinal chemistry Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 001063362300019 EID SCOPUS 85178022935 DOI 10.1093/pnasnexus/pgac297 Annotation 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 SCD153, 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2024 Electronic address https://doi.org/10.1093/pnasnexus/pgac297
Number of the records: 1