Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action

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.

Design of Hedgehog pathway inhibitors for cancer treatment

“…Mechanistic study of the active compounds revealed that noncyclohexyl thiophene analogs inhibited the Hh signaling via a PDE4-independent mechanism that functions in between SMO and Sufu, whereas cyclohexyl thiophene analogs inhibited Hh signaling via a PDE4-dependent mechanism downstream of Sufu (Figure 3A). 48…”