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An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.

Abstract：

:Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation.

journal_name

Cell Rep

journal_title

Cell reports

authors

Williams CH,Hempel JE,Hao J,Frist AY,Williams MM,Fleming JT,Sulikowski GA,Cooper MK,Chiang C,Hong CC

doi

10.1016/j.celrep.2015.03.001

subject

Has Abstract

pub_date

2015-04-07 00:00:00

pages

43-50

issue

1

issn

2211-1247

pii

S2211-1247(15)00243-0

journal_volume

11

pub_type

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