Furthermore, we studied the structure-activity relationship of the pyrimidine ( 7) derivatives and identified a potent compound ( 7_3d3) with IC 50 of 0.4 ± 0.1 μM in cellular assays. The compounds were verified to modulate the Hh pathway activity.
Seven compounds ( 1-7) with diverse scaffolds, showed inhibition in cellular assays and directly bound to ShhN in vitro. In this paper, we computationally screened potential inhibitors against the ShhN-Ptch interaction interface, and tested their activities by experimental studies. However, research of ShhN inhibitors remains lacking. Inhibitors that bind to ShhN and break its interaction with the 12-transmembrane glycoprotein patched (Ptch) protein are highly wanted to tune down the abnormal Hh pathway activation. The upstream protein, N-terminal product of sonic hedgehog (ShhN) is overexpressed in many cancers and considered as a promising antitumor target. The aberrant activation of hedgehog (Hh) signaling pathway is closely related to human diseases. 2Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Taikangxiang Yun 1, Juan Wang 2, Jun Yang 2, Wenjing Huang 2, Luhua Lai 1, Wenfu Tan 2 * and Ying Liu 1 *
