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Tevlin, R. et al. Pharmacological rescue of diabetic skeletal stem cell niches. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aag2809 (2017). Abundant evidences demonstrate that excessive Hh signaling induce the development of many cancers such as the advanced BCC and MB. The seven-transmembrane protein Smo is the main transducer of Hh signaling pathway and can be used as an important drug target. Therefore, many Smo inhibitors have been under investigation in clinical trials. Among them, GDC-0449 (vismodegib) and LDE-225 (sonidegib) were approved by FDA for treatment of advanced BCC in 2012 and 2015, respectively. As we known, acquired drug resistance is the main obstacle of first generation of Smo inhibitors. According to the clinical trials, GDC-0449 and LDE-225 emerged drug resistance because of the D473H mutation in Smo [ 27, 39]. Thus far, there are no available drugs for treatment of Hh-related diseases, which inspires a surge of Smo inhibitor researches.

Oh, S., Kato, M., Zhang, C., Guo, Y. & Beachy, P. A. A comparison of Ci/Gli activity as regulated by Sufu in Drosophila and mammalian Hedgehog response. PLoS ONE 10, e0135804 (2015). This cookie is used by Issuu analytic system to gather information regarding visitor activity on Issuu products. Han, B. et al. FOXC1 activates Smoothened-independent Hedgehog signaling in basal-like breast cancer. Cell Rep. 13, 1046–1058 (2015).

Deshpande, I. et al. Smoothened stimulation by membrane sterols drives Hedgehog pathway activity. Nature 571, 284–288 (2019). Cells were harvested and extracted total RNA using the TRIzol reagent (Thermo), and reverse transcription was performed with PrimeScript™ RT reagent Kit (TaKaRa). Real-time PCR was carried out according to the protocol of the manufactory. The primers for real-time PCR were mouse Gli1, F: 5ʹ-CTCAAACTGCCCAGCTTAACC. Ptch is attracting more attention by its association with the most common cancer in humans. The structure of Ptch1 was reported recently ( Gong et al., 2018; Qi et al., 2018; Zhang et al., 2018; Qian et al., 2019) and our small molecule inhibitors of Shh/Ptch provide important clues for future investigation of Hh signaling. Conclusion

Many people put out a saucer of meat-based pet food for their garden friends. The hedgehog will treat this as a welcome supplement to its normal diet and will not go hungry if, for some reason, the food is not put out. Always make sure that a dish of water is available especially during the summer months or in extreme weather conditions. The transmembrane protein Smo is the main transducer of Hh signaling pathway and can be used as an important drug target [ 21, 22]. Thus far, there are many Smo inhibitors have been under investigation in clinical trials. Among them, GDC-0449 (vismodegib) was approved by FDA for treatment of advanced BCC in 2012 [ 23, 24, 25]. Unfortunately, a recurring case revealed the drug resistance to GDC-0449 due to Asp473 to His mutation (D473H) in Smo, which would suppress the interaction between drug and receptor [ 26, 27]. In addition, reports indicated that about 40% BCC patients acquired drug resistance carry the Smo mutations. Of these, 17% patients contained the Smo-D473H type [ 28]. Therefore, new Smo inhibitors that could inhibit wild-type and mutant receptors are essential for overcoming drug resistance. Xiao, X. et al. Cholesterol modification of Smoothened is required for Hedgehog signaling. Mol. Cell 66, 154–162 e110 (2017).Johnston, J. J. et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am. J. Hum. Genet. 76, 609–622 (2005). Arveseth, C. D. et al. Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits. PLoS Biol. 19, e3001191 (2021).