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Mohler, J. & Vani, K. Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila. Development 115, 957–971 (1992). Wang, C. et al. Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat. Commun. 5, 4355 (2014). For reasons of hygiene and safety, personal grooming products, cosmetics or items of intimate clothing cannot be returned.

St-Jacques B, Dassule HR, Karavanova I, Botchkarev VA, Li J, Danielian PS, et al. Sonic hedgehog signaling is essential for hair development. Curr Biol. 1998;8(19):1058–68. You can use any larger-sized box for this, using the instructions below. I used our old glass recycling box, which is no longer needed if you live in East Sussex. Long, T. et al. Structural basis for itraconazole-mediated NPC1 inhibition. Nat. Commun. 11, 152 (2020). Yang, Z. et al. Stromal Hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer. Dis. Model. Mech. 10, 39–52 (2017). In this study, we made use of the Smo/βarr2-GFP high-throughput assay platform, and screened Smo inhibitors in our propriety small molecules library with the concentration of 5 μM. Through this effort, we discovered several active hits under screening including 0025A. In the Smo/βarr2-GFP internalization assay, we found 0025A was the most effective antagonist and be able to inhibit the cellular puncta of βarr2-GFP at the nano level. In addition, when we used Shh-CM or SAG to enhance Gli1 transcription, we observed that 0025A can act as a potent inhibitor and dose-dependently inhibit target gene Gli1 expression. At the same time, we have confirmed that 0025A would act on Smo receptor to inhibit Hh signaling pathway. Moreover, this lead compound also could interact with mutated Smo-D473H in contrast to GDC-0449 demonstrated by using Bodipy-cyclopamine competition binding assay. 0025A will provide a new tool to study the Smo-D473H mediated drug resistance and a candidate to treat the drug resistance to improve the cancer therapeutic success.

Creanga, A. et al. Scube/You activity mediates release of dually lipid-modified Hedgehog signal in soluble form. Genes Dev. 26, 1312–1325 (2012). Shin, K. et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26, 521–533 (2014). A large plastic box is another option for the house, but make sure to cut an entrance and plenty of breathing holes. Camouflage the box in the same way, with logs and leaf litter. Wang J, Mook RA Jr, Lu J, Gooden DM, Ribeiro A, Guo A, et al. Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling. Bioorg Med Chem. 2012;20(22):6751–7. Hui, C. C. & Angers, S. Gli proteins in development and disease. Annu. Rev. Cell Dev. Biol. 27, 513–537 (2011).

Lettice, L. A. et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12, 1725–1735 (2003). Rudin, C. M. et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 361, 1173–1178 (2009). Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, et al. Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science. 2004;306(5705):2257–60. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3(12):903–11. Zhao, C. et al. Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells. Science https://doi.org/10.1126/science.aal3485 (2017).

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Raleigh, D. R. et al. Cilia-associated oxysterols activate Smoothened. Mol. Cell 72, 316–327.e5 (2018). Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).

The animal studies were performed as previously described [ 30]. Briefly, female C57BL/6 mice (aged 7 to 8 weeks) were shaved dorsal hair and the bottom half of shaved area was depilated with Nair for 2 min. After depilation, the mice were topically treated with 30 μL of 5 mM 0025A dissolved in a vehicle of 95% acetone/5% DMSO or the vehicle once daily for 14 consecutive days and observed the pigment formation and hair regrowth. During the experimental procedures, the mice were anesthetized by 3% isoflurane and the studies were performed according to the ethical principles of animal welfare of Beijing Institute of Neurosurgery. Statistical analysis Rodgers, U. R. et al. Characterization of Hedgehog acyltransferase inhibitors identifies a small molecule probe for Hedgehog signaling by cancer cells. ACS Chem. Biol. 11, 3256–3262 (2016). Liu, S. L. et al. Simultaneous in situ quantification of two cellular lipid pools using orthogonal fluorescent sensors. Angew. Chem. Int. Ed. Engl. 53, 14387–14391 (2014). Williams, K. P. et al. Functional antagonists of sonic hedgehog reveal the importance of the N terminus for activity. J. Cell Sci. 112, 4405–4414 (1999).Stapornwongkul, K. S. & Vincent, J. P. Generation of extracellular morphogen gradients: the case for diffusion. Nat. Rev. Genet. 22, 393–411 (2021). Kumar, N. et al. Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN. Proc. Natl Acad. Sci. USA 114, 6557–6562 (2017). Matusek, T. et al. The ESCRT machinery regulates the secretion and long-range activity of Hedgehog. Nature 516, 99–103 (2014). Okada, A. et al. Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444, 369–373 (2006). Huang, P. et al. Cellular cholesterol directly activates Smoothened in Hedgehog signaling. Cell 166, 1176–1187 e1114 (2016).

Daly, C. A., Hall, E. T. & Ogden, S. K. Regulatory mechanisms of cytoneme-based morphogen transport. Cell Mol. Life Sci. 79, 119 (2022). McGough, I. J. et al. Glypicans shield the Wnt lipid moiety to enable signalling at a distance. Nature 585, 85–90 (2020). Nachtergaele, S. et al. Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. Elife 2, e01340 (2013). Tabata, T., Eaton, S. & Kornberg, T. B. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Genes Dev. 6, 2635–2645 (1992). Originally discovered in Drosophila melanogaster, the evolutionarily conserved Hedgehog (Hh) signaling pathway plays critical roles in promoting embryonic development [ 1, 2]. Upon completing embryogenesis, this pathway mostly becomes dormant except in certain tissues and under specific conditions such as during hair follicle morphogenesis and tissue repair [ 3, 4]. It has reported that Hh signaling is essential for regulating growth and morphogenesis of hair follicle [ 5].

Qian, H. et al. Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm. Nat. Commun. 10, 2320 (2019). Milenkovic, L. et al. Single-molecule imaging of Hedgehog pathway protein Smoothened in primary cilia reveals binding events regulated by Patched1. Proc. Natl Acad. Sci. USA 112, 8320–8325 (2015).