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Soluble Adenylyl Cyclase (sAC) Inhibitors for the Treatment of Psoriasis
Weill Cornell Medicine
Small molecule
Dermatology
Pre-Clinical
• The Technology: sAC inhibitors that prevent the induction of Th17-mediated psoriasis when topically administered
• The Discovery: Th17 cell polarization and growth were prevented by loss of sAC activity
• Based on previous high throughput screening studies that identified LRE1 as an allosteric inhibitor of sAC, TDI chemists developed a series of potent analogs with <100 nM EC50 and attractive PK characteristics
• PoC Data: In a 7-day murine imiquimod (IMQ) induced psoriasis model, topically administered TDI-11861 (EC50=1 nM) showed comparable efficacy to steroid control clobetasol but without induction of weight loss
• Safety: No overt toxicity was observed in in vivo studies, and TDI-11861 showed no significant activity against >310 kinases or 47 other well-known targets
Jochen Buck, Lonny R. Levin, Jonathan Zippin
PCT Application Filed
• "Soluble adenylyl cyclase contributes to imiquimod‐mediated inflammation and is a potential therapeutic target in psoriasis". You, J. et al. Experimental Dermatology. (2023) https://doi.org/10.1111/exd.14811
• "Discovery of TDI-10229: a potent and orally bioavailable inhibitor of soluble adenylyl cyclase (SAC, ADCY10)". Fushimi, M. et al. ACS Medicinal Chemistry Letters, (2021) 12(8), 1283–1287. https://doi.org/10.1021/acsmedchemlett.1c00273
