Identification of small molecule antagonists of sonic hedgehog/heparin binding with activity in hedgehog functional assays.

ABSTRACT: Sonic hedgehog (Shh) is a morphogen with important roles in embryonic development and in the development of a number of cancers. Its activity is modulated by interactions with binding partners and co-receptors including heparin and heparin sulfate proteoglycans (HSPG). To identify antagonists of Shh/heparin binding, a diverse collection of 34,560 chemicals was screened in single point 384-well format. We identified and confirmed twenty six novel small molecule antagonists with diverse structures including four scaffolds that gave rise to multiple hits. Nineteen of the confirmed hits blocked binding of the N-terminal fragment of Shh (ShhN) to heparin with IC₅₀ values < 50 μM. In the Shh-responsive C3H10T1/2 cell model, four of the compounds demonstrated the ability to block ShhN-

SUBMITTER: Lamson DR 

PROVIDER: S-EPMC11486593 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature