Novel Inhibitors of TGF Signaling

 

 

Annulated 1,4-Dihydropyridines Cardiomyogenic Compounds

as Novel Inhibitors of TGFβ Signaling

 

 

 

A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface.

 

 

Because this is an unprecedented mechanism of action, we explored the series’ structure–activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs.

 

 

We determined a pharmacophore and generated 1,4-DHPs with IC₅₀s for TGFβ inhibition in the nanomolar range (e.g., compound 28, 170 nM).

 

 

Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (−) enantiomer.

 

 

This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.

 

 

 

 

http://pubs.acs.org/doi/abs/10.1021/jm301144g?prevSearch=TGF%25CE%25B2%2BInhibitor&searchHistoryKey=