Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata

Jerry Tsai; Sadakatali Gori; Jesse Alt; Sandhya Tiwari; Jitesh Iyer; Rashmi Talwar; Denish Hinsu; Kailash Ahirwar; Swayam Mohanty; Chintan Khunt; Brijesh Sutariya; Kaushal Jani; Venkatesha Venkatasubbaiah; Ashok Patel; Jasmin Meghapara; Kaushal Joshi; Rajanikanta Sahu; Vijay Rana; Prashant Nigade; Ravi S Talluri; Kadiyala V S N Murty; Kiritkumar Joshi; Vikram Ramanathan; Ang Li; Nasif Islam; Ivan Snajdr; Pavel Majer; Rana Rais; Barbara S Slusher; Luis A Garza

doi:10.1093/pnasnexus/pgac297

Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata

PNAS Nexus. 2022 Dec 16;2(1):pgac297. doi: 10.1093/pnasnexus/pgac297. eCollection 2023 Jan.

Authors

Jerry Tsai¹, Sadakatali Gori², Jesse Alt², Sandhya Tiwari³, Jitesh Iyer³, Rashmi Talwar³, Denish Hinsu⁴, Kailash Ahirwar⁵, Swayam Mohanty⁴, Chintan Khunt⁴, Brijesh Sutariya⁶, Kaushal Jani⁴, Venkatesha Venkatasubbaiah⁴, Ashok Patel⁷, Jasmin Meghapara⁷, Kaushal Joshi⁷, Rajanikanta Sahu⁷, Vijay Rana⁷, Prashant Nigade⁷, Ravi S Talluri⁸, Kadiyala V S N Murty⁹, Kiritkumar Joshi⁹, Vikram Ramanathan¹⁰, Ang Li¹, Nasif Islam¹, Ivan Snajdr¹¹, Pavel Majer¹¹, Rana Rais^{2

12

13}, Barbara S Slusher^{2

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13

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17}, Luis A Garza^{1

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18}

Affiliations

¹ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ In Vitro Biology, Sun Pharma Advanced Research Company, Savli, 391770, India.
⁴ Preclinical Pharmacology, Sun Pharma Advanced Research Company, Savli, 391770, India.
⁵ Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research Ahmedabad, Gandhinagar 382355, India.
⁶ Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, IA 52242, USA.
⁷ Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India.
⁸ Clinical Pharmacology, Sun Pharma Advanced Research Company, Mahakali, Mumbai 400093, India.
⁹ Medicinal Chemistry, Sun Pharma Advanced Research Company, Savli 391770, India.
¹⁰ Translational Development, Sun Pharma Advanced Research Company, Savli 391770, India.
¹¹ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 166 10, Czech Republic.
¹² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹³ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁶ Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
¹⁷ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁸ Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205, USA.

Abstract

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.

Keywords: alopecia areata; anagen; cytokine; cytotoxicity; double-stranded RNA; hair cycle; hair growth; immunosuppression; inflammation; interferon; interleukin; itaconate; keratinocyte; pharmacokinetics; polyinosinic–polycytidylic acid; prodrug; stability; telogen; topical.