Discovery of Small Molecule Inhibitors Targeting the Sonic Hedgehog

Taikangxiang Yun; Juan Wang; Jun Yang; Wenjing Huang; Luhua Lai; Wenfu Tan; Ying Liu

doi:10.3389/fchem.2020.00498

Discovery of Small Molecule Inhibitors Targeting the Sonic Hedgehog

Front Chem. 2020 Jun 16:8:498. doi: 10.3389/fchem.2020.00498. eCollection 2020.

Authors

Taikangxiang Yun¹, Juan Wang², Jun Yang², Wenjing Huang², Luhua Lai¹, Wenfu Tan², Ying Liu¹

Affiliations

¹ Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, College of Chemistry and Molecular Engineering, Beijing National Laboratory for Molecular Sciences (BNLMS), Peking University, Beijing, China.
² Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.

Abstract

The aberrant activation of hedgehog (Hh) signaling pathway is closely related to human diseases. The upstream protein, N-terminal product of sonic hedgehog (ShhN) is overexpressed in many cancers and considered as a promising antitumor target. 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. However, research of ShhN inhibitors remains lacking. In this paper, we computationally screened potential inhibitors against the ShhN-Ptch interaction interface, and tested their activities by experimental studies. Seven compounds (1-7) with diverse scaffolds, showed inhibition in cellular assays and directly bound to ShhN in vitro. The compounds were verified to modulate the Hh pathway activity. Furthermore, we studied the structure-activity relationship of the pyrimidine (7) derivatives and identified a potent compound (7_3d3) with IC₅₀ of 0.4 ± 0.1 μM in cellular assays. These small molecule inhibitors of ShhN provide novel chemical probes for future investigations of Hh signaling.

Keywords: N-terminal product of sonic hedgehog; Shh/Ptch interface; hedgehog signaling pathway; small molecule inhibitor; structure activity analysis; virtual screening.