Eclitasertib

Eclitasertib is an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1; IC₅₀ = 0.0375 µM).¹ It inhibits necroptosis induced by TNF-α, a Smac mimetic, and Z-VAD-FMK in HT-29 cells (EC₅₀ = 0.0154 µM, respectively).² Eclitasertib (4 nM) inhibits necroptosis induced by IFN-γ, TNF-α, Z-VAD, and an Smac mimetic and reduces cytokine levels induced by the same combination in primary human keratinocytes.³ It reduces epidermal thickness, reverses disruptions in epidermal architecture, and reduces IL-1 receptor A (IL-1RA) release in 3D keratinocyte skin equivalents generated from primary human keratinocytes and stimulated with mixed lesional T cell supernatants prepared from lichen planus (LP) and cutaneous lupus erythematosus (CLE) patient-derived skin biopsies. Eclitasertib (1 mg/kg) reverses TNF-α- and Z-VAD-induced hypothermia in a mouse model of systemic inflammatory response syndrome.

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1. Darwish, I., Luo, Z., and Taylor, V. RIP1K inhibitors. WO2021203011A1, (2021).

2. Xia, C., Yao, Z., Xu, L., et al. Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors. Eur. J. Med. Chem. 220, 113484 (2021).

3. Jargosch, M., Wasserer, S., Eigemann, J., et al. Inhibition of RIPK1 prevents keratinocyte cell death and reduces skin inflammation in type 1–mediated chronic inflammatory skin diseases. J. Allergy Clin. Immunol. S0091-6749(0026)00087-00084 (2026).