2. Academic Validation
  3. Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action

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

  • Bioorg Med Chem Lett. 2016 Apr 15;26(8):1947-53. doi: 10.1016/j.bmcl.2016.03.013.
Jonathan E Hempel 1,  Adrian G Cadar 2,  Charles C Hong 3
Affiliations

Affiliations

  • 1 Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, PRB 383, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, 896 Preston Research Building, Nashville, TN 37232, USA.
  • 2 Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, PRB 383, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 702 Light Hall, Nashville, TN 37232, USA.
  • 3 Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, PRB 383, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, 896 Preston Research Building, Nashville, TN 37232, USA; Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address: charles.c.hong@vanderbilt.edu.
PMID: 26976215 DOI: 10.1016/j.bmcl.2016.03.013
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.

Keywords

Eggmanone; Hedgehog signaling pathway; Phenotypic screening; Probe development; Suppressor of Fused.

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