SIG1459: A novel phytyl-cysteine derived TLR2 modulator with in vitro and clinical anti-acne activity.

TitleSIG1459: A novel phytyl-cysteine derived TLR2 modulator with in vitro and clinical anti-acne activity.
Publication TypeJournal Article
Year of Publication2018
AuthorsFernández, JR, Webb, C, Rouzard, K, Healy, J, Tamura, M, Voronkov, M, Huber, KL, Stock, JB, Stock, M, Gordon, JS, Pérez, E
JournalExp Dermatol
Date Published2018 May 24

Cutibacterium (formerly Propionibacterium) acnes is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll-like receptor-2 (TLR2) a key step in comedogenesis. Tetramethyl-hexadecenyl-cysteine-formylprolinate (SIG1459) a novel anti-acne isoprenylcysteine (IPC) small molecule is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signaling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 μM) minimal bactericidal concentration (MBC = 16.1 μM) and minimal biofilm eradication concentration (MBEC = 12.5 μM). To assess SIG1459's anti-inflammatory activity human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan FSL-1 Pam3CSK4) that induce pro-inflammatory cytokine IL-8 and IL-1α production. Results demonstrate SIG1459 inhibits TLR2 induced IL-8 release from TLR2/TLR2 (IC = 0.086 μM) TLR2/6 (IC = 0.209 μM) and IL-1α from TLR2/TLR2 (IC = 0.050 μM). To assess the safety and in vivo anti-acne activity of SIG1459 a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n=35 subjects) in a head-to-head comparison against 3% BPO (n=15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks resulting in 79% improvement as compared to 56% for BPO. Additionally 1% SIG1459 was well tolerated. Thus SIG1459 and phytyl IPC compounds represent a novel anti-acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signaling. This article is protected by copyright. All rights reserved.

Alternate JournalExp. Dermatol.
PubMed ID29797368