Yun Taikangxiang, Wang Juan, Yang Jun, Huang Wenjing, Lai Luhua, Tan Wenfu, Liu Ying
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.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Front Chem. 2020 Jun 16;8:498. doi: 10.3389/fchem.2020.00498. eCollection 2020.
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 () with diverse scaffolds, showed inhibition in cellular assays and directly bound to ShhN . The compounds were verified to modulate the Hh pathway activity. Furthermore, we studied the structure-activity relationship of the pyrimidine () derivatives and identified a potent compound () with IC 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.
刺猬信号通路（Hh）的异常激活与人类疾病密切相关。其上游蛋白，即音猬因子（Shh）的N端产物（ShhN）在许多癌症中过表达，被认为是一个有前景的抗肿瘤靶点。迫切需要能够与ShhN结合并破坏其与12次跨膜糖蛋白patched（Ptch）蛋白相互作用的抑制剂，以降低异常的Hh信号通路激活。然而，关于ShhN抑制剂的研究仍然匮乏。在本文中，我们通过计算机筛选针对ShhN-Ptch相互作用界面的潜在抑制剂，并通过实验研究测试它们的活性。七种具有不同骨架的化合物（）在细胞实验中显示出抑制作用，并直接与ShhN结合。这些化合物被证实可调节Hh信号通路活性。此外，我们研究了嘧啶（）衍生物的构效关系，并确定了一种在细胞实验中IC为0.4±0.1μM的强效化合物（）。这些ShhN小分子抑制剂为未来Hh信号研究提供了新的化学探针。
