Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Hempel, Jonathan E.; Cadar, Adrian G.; Hong, Charles C.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 8(2016)
• Page Start: 1947
• Page End: 1953
• Publication Date: 2016-04-15
• Subjects: Hedgehog signaling pathway -- Eggmanone -- Suppressor of Fused -- Phenotypic screening -- Probe development; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.03.013
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: From a high content in vivo screen for modulators of developmental patterning in embryonic zebrafish, we previously identified eggmanone (EGM1, 3 ) as a Hedgehog (Hh) signaling inhibitor functioning downstream of Smoothened. Phenotypic optimization studies for in vitro probe development utilizing a Gli transcription-linked stable luciferase reporter cell line identified EGM1 analogs with improved potency and aqueous solubility. Mechanistic profiling of optimized analogs indicated two distinct scaffold clusters: PDE4 inhibitors able to inhibit downstream of Sufu, and PDE4-independent Hh inhibitors functioning between Smo and Sufu. Each class represents valuable in vitro probes for elucidating the complex mechanisms of Hh regulation.