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To gain further insight into the effects of inhibitors against ShhN, a NanoDSF experiment was conducted. The results indicated that 7_3d3 improved the thermal stability of ShhN better than 7 ( Figure S3), indicating an interaction of 7_3d3 toward ShhN in vitro. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014). Teglund S, Toftgård R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta. 2010;1805(2):181–208. Yamaguchi, A., Nakashima, R. & Sakurai, K. Structural basis of RND-type multidrug exporters. Front. Microbiol. 6, 327 (2015).

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Qian, H. et al. Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm. Nat. Commun. 10, 2320 (2019). Chuang, P. T. & McMahon, A. P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999).

Briscoe, J. & Small, S. Morphogen rules: design principles of gradient-mediated embryo patterning. Development 142, 3996–4009 (2015). Porter, J. A., Young, K. E. & Beachy, P. A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274, 255–259 (1996). Griffiths, S. C. et al. Hedgehog-interacting protein is a multimodal antagonist of Hedgehog signalling. Nat. Commun. 12, 7171 (2021). Buonamici, S. et al. Interfering with resistance to Smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2, 51ra70 (2010). Yang, Z. et al. Stromal Hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer. Dis. Model. Mech. 10, 39–52 (2017).Nachtergaele, S. et al. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat. Chem. Biol. 8, 211–220 (2012). Myers, B. R., Neahring, L., Zhang, Y., Roberts, K. J. & Beachy, P. A. Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. Proc. Natl Acad. Sci. USA 114, E11141–E11150 (2017). In the R2 region, when the central framework was changed to fused 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (from 7_3d1 to 7_3d6), the inhibitory activities were greatly increased. Strikingly, the IC 50 value of 7_3d3 reached at about 0.4 μM, which is currently the most active small molecule. In 7_3d3, the hydrogen atom of the amino-group was replaced by a large hydrophobic halogenated benzene ( Figure S2). The fused ring, 1H-pyrazolo[3,4-d]pyrimidine presents a novel framework of the inhibitors. The other five compounds identified through 3D similarity search have central frameworks that are similar to that of 5-nitropyrimidine-2, 4, 6-triamine, among which only 7_3d11 showed better potency.