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Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design

  • Fabrizio ManettiEmail author
  • Maurizio Taddei
  • Elena Petricci
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 16)

Abstract

Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation or inhibition is considered a potential powerful tool in regenerative medicine and for the treatment of cancer. In the last years, many natural and nonnatural small molecules have been identified that are able to modulate the Hh pathway. Most of them target Smo, while only a few compounds are able to interact directly with upstream and downstream Hh pathway components. Although several compounds showed a remarkable potency and selectivity, their use induced emergence of mutated and resistant cell lines. In an attempt to find new chemical entries able to affect the Hh pathway and overcome limitation imposed by mutations and resistance, academic researchers and pharmaceutical companies are making further efforts to identify new drug-like small molecules to be included in the currently available therapeutic protocols for several types of cancers or in regenerative medicine and tissue repair.

Keywords

Hedgehog signaling Hit-to-lead compound optimization Small molecule Smoothened antagonists and agonists Structure–activity relationships Synthesis 

Abbreviations

Adh7

Alcohol dehydrogenase 7

ADMETox

Absorption, distribution, metabolism, excretion, toxicity

AP

Alkaline phosphatase

APL

Acute promyelocytic leukemia

BCC

Basal cell carcinoma

BODIPY

Boron dimethylpyrrolydene

CML

Chronic myelogenous leukemia

CRD

Cysteine-rich domain

Cyp24A1

Cytochrome P24A1

Cyp450

Cytochrome P450

Dhh

Desert Hedgehog

DOS

Diversity-oriented synthesis

EC50

Half-maximal effective concentration

FDA

Food and Drug Administration

FRET

Fluorescence resonance energy transfer

GANT

Glioma-associated oncogene homologue (Gli) antagonist

GCP

Granular cell precursor

GFP

Green fluorescent protein

GI50

50% inhibition of cell growth

Gli1-3

Glioma-associated oncogene homologue 1–3

Gli-Luc assay

Glioma-associated oncogene homologue-luciferase assay

GPCR

G protein-coupled receptor

h

Hour

HEPM

Human embryonic palatal mesenchymal cells

hERG

Human ether-à-go-go-related gene

Hh

Hedgehog

Hh-Ag

Hedgehog agonist

Hh-Antag691

Hedgehog antagonist 691

HPI

Hedgehog pathway inhibitors

HTS

High-throughput screening

IC50

Half-maximal inhibitory concentration

Ihh

Indian Hedgehog

KAAD-cyclopamine

3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)cyclopamine

LiHMDS

Lithium bis(trimethylsilyl)azanide

MAPK

Mitogen-activated protein kinase

MeI

Methyl iodide

mL

Milliliter

nM

Nanomolar

PBO

Piperonyl butoxide

PKC

Protein kinase C

PSA

Prostate specific antigen

Ptch

Patched

PXR

Pregnane X receptor

Ren

Retinoic acid, epidermal growth factor, nerve growth factor induced gene protein

SAG

Smoothened agonist

SANT

Smoothened antagonist

SAR

Structure–activity relationships

SFC

Supercritical fluid chromatography

Shh

Sonic Hedgehog

ShhN

N-terminal tail of sonic Hedgehog

SMANT

Smoothened mutant antagonist

Smo

Smoothened

SmoM2

Oncogenic Smoothened (Smo) mutant

SuFu

Suppressor of fused

TM

Transmembrane helix

VD2

Vitamin D2

VD3

Vitamin D3

VDR

Vitamin D receptor

μg

Microgram

μM

Micromolar

References

  1. 1.
    McMillan R, Matsui W (2012) Molecular pathways: the Hedgehog signaling pathway in cancer. Clin Cancer Res 18:4883–4888Google Scholar
  2. 2.
    Scales SJ, de Sauvage FJ (2009) Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30:303–312Google Scholar
  3. 3.
    Amakye D, Jagani Z, Dorsch M (2013) Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med 19:1410–1422Google Scholar
  4. 4.
    Yun JI, Kim HR, Park H, Kim SK, Lee J (2012) Small molecule inhibitors of the Hedgehog signaling pathway for the treatment of cancer. Arch Pharm Res 35:1317–1333Google Scholar
  5. 5.
    Peukert S, Miller-Moslin K (2010) Small-molecule inhibitors of the Hedgehog signaling pathway as cancer therapeutics. ChemMedChem 5:500–512Google Scholar
  6. 6.
    Tremblay MR, McGovern K, Read MA, Castro AC (2010) New developments in the discovery of small molecule Hedgehog pathway antagonists. Curr Opin Chem Biol 14:428–435Google Scholar
  7. 7.
    Mahindroo N, Punchihewa C, Fujii N (2009) Hedgehog-Gli signaling pathway inhibitors as anticancer agents. J Med Chem 52:3829–3845Google Scholar
  8. 8.
    Lin TL, Matsui W (2012) Hedgehog pathway as a drug target: smoothened inhibitors in development. OncoTargets Ther 5:47–58Google Scholar
  9. 9.
    Hadden MK (2014) Hedgehog pathway agonism: therapeutic potential and small-molecule development. ChemMedChem 9:27–37Google Scholar
  10. 10.
    Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol BioSyst 6:44–54Google Scholar
  11. 11.
    Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (2000) Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature 406:1005–1009Google Scholar
  12. 12.
    Hamon F, Renoux B, Chadeneau C, Muller J-M, Papot S (2010) Study of a cyclopamine glucuronide prodrug for the selective chemotherapy of glioblastoma. Eur J Med Chem 45:1678–1682Google Scholar
  13. 13.
    Renoux B, Legigan T, Bensalma S, Chadeneau C, Muller J-M, Papot S (2011) A new cyclopamine glucuronide prodrug with improved kinetics of drug release. Org Biomol Chem 9:8459–8464Google Scholar
  14. 14.
    Kumar SK, Roy I, Anchoori RK, Fazli S, Maitra A, Beachy PA, Khan SR (2008) Targeted inhibition of Hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg Med Chem 16:2764–2768Google Scholar
  15. 15.
    Tremblay MR, Nevalainen M, Nair SJ, Porter JR, Castro AC, Behnke ML, Yu L-C, Hagel M, White K, Faia K, Grenier L, Campbell MJ, Cushing J, Woodward CN, Hoyt J, Foley MA, Read MA, Sydor JR, Tong JK, Palombella VJ, McGovern K, Adams J (2008) Semisynthetic cyclopamine analogues as potent and orally bioavailable Hedgehog pathway antagonists. J Med Chem 51:6646–6649Google Scholar
  16. 16.
    Feldmann G, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H, Koorstra J-BM, Habbe N, Karikari C, Mullendore M, Gabrielson KL, Sharma R, Matsui W, Maitra A (2008) An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther 7:2725–2735Google Scholar
  17. 17.
    Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC, Yu L-C, Behnke ML, Nair SJ, Hagel M, White K, Conley J, Manna JD, Alvarez-Diez TM, Hoyt J, Woodward CN, Sydor JR, Pink M, McDougall J, Campbell MJ, Cushing J, Ferguson J, Curtis MS, McGovern K, Read MA, Palombella VJ, Adams J, Castro AC (2009) Discovery of a potent and orally active Hedgehog pathway antagonist (IPI-926). J Med Chem 52:4400–4418Google Scholar
  18. 18.
    Lee MJ, Hatton BA, Villavicencio EH, Khanna PC, Friedman SD, Ditzler S, Pullar B, Robison K, White KF, Tunkey C, LeBlanc M, Randolph-Habecker J, Knoblaugh SE, Hansen S, Richards A, Wainwright BJ, McGovern K, Olson JM (2012) Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc Natl Acad Sci USA 109:7859–7864Google Scholar
  19. 19.
    Moschner J, Chentsova A, Eilert N, Rovardi I, Heretsch P, Giannis A (2013) Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of Hedgehog signaling. Beilstein J Org Chem 9:2328–2335Google Scholar
  20. 20.
    Winkler JD, Isaacs A, Holderbaum L, Tatard V, Dahmane N (2009) Design and synthesis of inhibitors of Hedgehog signaling based on the alkaloid cyclopamine. Org Lett 11:2824–2827Google Scholar
  21. 21.
    Guerlet G, Spangenberg T, Mann A, Faure H, Ruat M (2011) Synthesis and biological evaluation of desmethylveramiline, a micromolar Hedgehog inhibitor. Bioorg Med Chem Lett 21:3608–3612Google Scholar
  22. 22.
    Lipinski RJ, Dengler E, Kiehn M, Peterson RE, Bushman W (2007) Identification and characterization of several dietary alkaloids as weak inhibitors of Hedgehog signaling. Toxicol Sci 100:456–463Google Scholar
  23. 23.
    Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP (2006) Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PloS Biol 4:e232Google Scholar
  24. 24.
    Teichert AE, Elalieh H, Elias PM, Welsh J, Bikle DD (2011) Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice. J Invest Dermatol 131:2289–2297Google Scholar
  25. 25.
    Banerjee U, Ghosh M, Hadden MK (2012) Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors. Bioorg Med Chem Lett 22:1330–1334Google Scholar
  26. 26.
    DeBerardinis AM, Banerjee U, Miller M, Lemieux S, Hadden MK (2012) Probing the structural requirements for vitamin D3 inhibitors of the Hedgehog signaling pathway. Bioorg Med Chem Lett 22:4859–4863Google Scholar
  27. 27.
    DeBerardinis AM, Banerjee U, Hadden MK (2013) Identification of vitamin D3-based Hedgehog pathway inhibitors that incorporate an aromatic A-ring isostere. ACS Med Chem Lett 4:590–595Google Scholar
  28. 28.
    DeBerardinis AM, Madden DJ, Banarjee U, Sail V, Raccuia DS, De Carlo D, Lemieux SM, Meares A, Hadden MK (2014) Structure–activity relationships for vitamin D3-based aromatic A-ring analogues as Hedgehog pathway inhibitors. J Med Chem 57(9):3724–3736Google Scholar
  29. 29.
    Baxter AD, Boyd EA, Guicherit OM, Price S, Rubin LL (2001) Mediators of the Hedgehog signaling pathways, compositions and uses related thereto. WO 26644 A2Google Scholar
  30. 30.
    Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Nusse R, Porter JA, Rubin LL, Wang FY (2003) Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci USA 100:4616–4621Google Scholar
  31. 31.
    Tang T, Tang JY, Li D, Reich M, Callahan CA, Fu L, Yauch RL, Wang F, Kotkow K, Chang KS, Shpall E, Wu A, Rubin LL, Marsters JC Jr, Epstein EH Jr, Caro I, de Sauvage FJ (2011) Targeting superficial or nodular basal cell carcinoma with topically formulated small molecule inhibitor of smoothened. Clin Cancer Res 17:3378–3387Google Scholar
  32. 32.
    Rubin L, Giucherit OM, Price S, Boyd EA (2003) Mediators of Hedgehog signaling pathways, compositions and uses related thereto. WO 011219 A2Google Scholar
  33. 33.
    Gunzner JL, Sutherlin D, Stanley MS, Bao L, Castanedo GM, LaLonde RL, Wang S, Reynolds ME, Savage SJ, Malesky K, Dina MS (2006) Pyridyl inhibitors of Hedgehog signalling. US 0063779 A1Google Scholar
  34. 34.
    Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W, Khojasteh C, Koehler MFT, Kotkow K, La H, LaLonde RL, Lau K, Lee L, Marshall D, Marsters J Jr, Murray LJ, Qian C, Rubin LL, Salphati L, Stanley MS, Stibbard JHA, Sutherlin DP, Ubhayaker S, Wang S, Wong S, Xie M (2009) GDC-0449 – a potent inhibitor of the Hedgehog pathway. Bioorg Med Chem Lett 19:5576–5581Google Scholar
  35. 35.
    Castanedo GM, Wang S, Robarge KD, Balckwood E, Burdick D, Chang C, Dijkgraaf GJP, Gould S, Gunzner J, Guichert O, Halladay J, Khojasteh C, Lee L, Marsters JC Jr, Murray L, Peterson D, Plise E, Salphati L, de Sauvage FJ, Wong S, Sutherlin DP (2010) Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway. Bioorg Med Chem Lett 20:6748–6753Google Scholar
  36. 36.
    Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178Google Scholar
  37. 37.
    Asklund T, Henriksson R, Axelsson J, Bergstrom A, Kasper M, Ogren M, Toftgard R, Riklund KA (2013) Early and persisting response to vismodegib in a patient with bone metastasizing medulloblastoma. Acta Oncol 52:862–866Google Scholar
  38. 38.
    Atwood SX, Chang AL, Oro AE (2012) Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol 199:193–197Google Scholar
  39. 39.
    Yauch RL, Dijkgraaf GJP, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574Google Scholar
  40. 40.
    Dijkgraaf GJP, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Bobarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, de Sauvage FJ (2011) Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res 71:435–444Google Scholar
  41. 41.
    Baxter AD, Boyd EA, Guicherit OM, Price S, Rubin LD (2001) Mediators of the Hedgehog signaling pathways, compositions and uses related thereto. WO 019800 A3Google Scholar
  42. 42.
    Brunton SA, Stibbard JHA, Rubin LL, Kruse LI, Guicherit OM, Boyd EA, Price S (2008) Potent inhibitors of the Hedgehog signaling pathway. J Med Chem 51:1108–1110Google Scholar
  43. 43.
    Thomas RJ, Pericot Mohr G, Minetto G, Bakker A, Ferruzzi P (2009) The hedgehog pathway antagonists and therapeutic thereof. WO 074300 A2Google Scholar
  44. 44.
    Tunici P, Mancuso M, Giordano C, Ferruzzi P, Mennillo F, Tanori M, Saran A, Thomas R, Pericot Mohr G, Bakker A (2011) Selective smoothened antagonists for anti-tumor therapy. In: Proceedings of the 102nd annual meeting of the American Association for cancer research; 2011 April 2–6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011, 71, Abstract number LB-38Google Scholar
  45. 45.
    Ferruzzi P, Mennillo F, De Rosa A, Giordano C, Rossi M, Benedetti G, Magrini R, Pericot Mohr G, Miragliotta V, Magnoni L, Mori E, Thomas R, Tunici P, Bakker A (2012) In vitro and in vivo characterization of a novel Hedgehog signaling antagonist in human glioblastoma cell lines. Int J Cancer 131:E33–E44Google Scholar
  46. 46.
    Dessole G, Branca D, Ferrigno F, Kinzel O, Muraglia E, Palumbi MC, Rowley M, Serafini S, Steinkuhler C, Jones P (2009) Discovery of N-[(1-aryl-1H-indazol-5-yl)methyl]amides derivatives as smoothened antagonists for inhibition of the hedgehog pathway. Bioorg Med Chem Lett 19:4191–4195Google Scholar
  47. 47.
    Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang FY, Jones S, Shulok J, Rubin LL, Porter JA (2002) Small-molecule modulators of Hedgehog signaling: identification and characterization of smoothened agonists and antagonists. J Biol 1:10Google Scholar
  48. 48.
    Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev 16:2743–2748Google Scholar
  49. 49.
    Malancona S, Altamura S, Filocamo G, Kinzel O, Hernando JIM, Rowley M, Scarpelli R, Steinkuhler C, Jones P (2011) Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 1. Bioorg Med Chem Lett 21:4422–4428Google Scholar
  50. 50.
    Kinzel O, Alfieri A, Altamura S, Brunetti M, Bufali S, Colaceci F, Ferrigno F, Filocamo G, Fonsi M, Gallinari P, Malancona S, Hernando JIM, Monteagudo E, Orsale MV, Palumbi MC, Pucci V, Rowley M, Sasso R, Scarpelli R, Steinkuhler C, Jones P (2011) Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2. Bioorg Med Chem Lett 21:4429–4435Google Scholar
  51. 51.
    Ontoria JM, Llauger Bufi L, Torrisi C, Bresciani A, Giomini C, Rowley M, Serafini S, Bin H, Hao W, Steinkuhler C, Jones P (2011) Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors. Bioorg Med Chem Lett 21:5274–5282Google Scholar
  52. 52.
    Muraglia E, Ontoria JM, Branca D, Dessole G, Bresciani A, Fonsi M, Giuliano C, Llauger Bufi L, Monteagudo E, Palumbi MC, Torrisi C, Rowley M, Steinkuhler C, Jones P (2011) N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists. Bioorg Med Chem Lett 21:5283–5288Google Scholar
  53. 53.
    Balkovec JM, Thieringer R, Waddell ST (2008) Triazole derivatives which are Smo antagonists. WO 130552 A1Google Scholar
  54. 54.
    Austin RJ, Kaizerman JA, Lucas BS, McMinn DL, Powers JP (2009) Phthalazine compounds, compositions and methods of use. WO 002469 A1Google Scholar
  55. 55.
    Lucas BS, Aaron W, An S, Austin RJ, Brown M, Chan H, Chong A, Hungate R, Huang T, Jiang B, Johnson MG, Kaizerman JA, Lee G, McMinn DL, Orf J, Powers JP, Rong M, Toteva MM, Uyeda C, Wickramasinghe D, Xu G, Ye Q, Zhong W (2010) Design of 1-piperazinyl-4-arylphthalazines as potent smoothened antagonists. Bioorg Med Chem Lett 20:3618–3622Google Scholar
  56. 56.
    Kaizerman JA, Lucas BS, McMinn DL, Zamboni R (2009) Annelated pyridazines for the treatment of tumors driven by inappropriate Hedgehog signaling. WO 035568 A1Google Scholar
  57. 57.
    Kaizerman JA, Aaron W, An S, Austin RJ, Brown M, Chong A, Huang T, Hungate R, Jiang B, Johnson MG, Lee G, Lucas BS, Orf J, Rong M, Toteva MM, Wickramasinghe D, Xu G, Ye Q, Zhong W, McMinn DL (2010) Addressing PXR liability of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines. Bioorg Med Chem Lett 20:4607–4610Google Scholar
  58. 58.
    Brown ML, Aaron W, Austin RJ, Chong A, Huang T, Jiang B, Kaizerman JA, Lee G, Lucas BS, McMinn DL, Orf J, Rong M, Toteva MM, Xu G, Ye Q, Zhong W, DeGraffenreid MR, Wickramasinghe D, Powers JP, Hungate R, Johnson MG (2011) Discovery of amide replacement that improve activity and metabolic stability of a bis-amide smoothened antagonist hit. Bioorg Med Chem Lett 21:5206–5209Google Scholar
  59. 59.
    Miller-Moslin K, Peukert S, Jain RK, McEwan MA, Karki R, Llamas L, Yusuff N, He F, Li Y, Sun Y, Dai M, Perez L, Michael W, Sheng T, Lei H, Zhang R, Williams J, Bourret A, Ramamurthy A, Yuan J, Guo R, Matsumoto M, Vattay A, Maniara W, Amaral A, Dorsch M, Kelleher JF 3rd (2009) 1-Amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. J Med Chem 52:3954–3968Google Scholar
  60. 60.
    Peukert S, He F, Dai M, Zhang R, Sun Y, Miller-Moslin K, McEwan M, Lagu B, Wang K, Yusuff N, Bourret A, Ramamurthy A, Maniara W, Amaral A, Vattay A, Wang A, Guo R, Yuan J, Green J, Williams J, Buonamici S, Kelleher JF 3rd, Dorsch M (2013) ChemMedChem 8:1261–1265Google Scholar
  61. 61.
    Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, Han D, Liu J, Englund NP, Wan Y, Peukert S, Miller-Moslin K, Yuan J, Guo R, Matsumoro M, Vattay A, Jiang Y, Tsao J, Sun F, Pferdekamper AC, Dodd S, Tuntland T, Maniara W, Kelleher 3rd JF, Yao Y, Warmuth M, Williams J, Dorsch M (2010) Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett 1:130–134Google Scholar
  62. 62.
    Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, Hsiao K, Yuan J, Green J, Ospina B, Yu Q, Ostrom L, Fordjour P, Anderson DL, Monahan JE, Kelleher JF, Peukert S, Pan S, Wu X, Maira SM, García-Echeverría C, Briggs KJ, Watkins DN, Yao YM, Lengauer C, Warmuth M, Sellers WR, Dorsch M (2010) Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med 2:51ra70Google Scholar
  63. 63.
    Cheng D, Han D, Gao W, Jing Q, Jiang J, Wan Y, Englund NP, Tuntland T, Wu X, Pan S (2012) Design, synthesis, and structure-activity-relationship of phenyl imidazoles as potent smoothened antagonists. Bioorg Med Chem Lett 22:6573–6576Google Scholar
  64. 64.
    Peukert S, Jain RK, Geisser A, Sun Y, Zhang R, Bourret A, Carlson A, DaSilva J, Ramamurthy A, Kelleher JF (2009) Identification and structure–activity relationships of ortho-biphenyl carboxamides as potent smoothened antagonists inhibiting the Hedgehog signaling pathway. Bioorg Med Chem Lett 19:328–331Google Scholar
  65. 65.
    Hipskind PA, Takakuwa T (2009) Disubstituted phthalazine Hedgehog pathway antagonists. WO 134574 A2Google Scholar
  66. 66.
    Bender MH, Hipskind PA, Capen AR, Cockman M, Credille KM, Gao H, Bastina JA, Clay JM, Lobb KL, Sall DJ, Thompson ML, Wilson T, Wishart GN, Patel BKR (2011) Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling. In: Proceedings of the 102nd annual meeting of the American Association for Cancer Research; 2011 April 2–6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011, 71, Abstract number 2819Google Scholar
  67. 67.
    Wang C, Wu X, Katritch V, Han GW, Huang X-P, Liu W, Siu FY, Roth BL, Cherezov V, Stevens RC (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497:338–343Google Scholar
  68. 68.
  69. 69.
    Bahceci S, Bajjalieh W, Chen J, Epshteyn S, Forsyth TP, Huynh TP, Kim BG, Leahy JW, Lee MS, Lewis GL, Mac MB, Mann G, Marlowe CK, Ridgway BH, Sangalang JC, Shi X, Rakeuchi CS, Wang Y (2008) Inhibitors of the Hedgehog pathway. WO 112913 A1Google Scholar
  70. 70.
    Rocconi RP, Samant L (2013) Methods and compositions for the treatment of ovarian cancer. WO 043255 A1Google Scholar
  71. 71.
    http://www.exelixis.com/pipeline/xl139. Accessed 26 February 2014
  72. 72.
    Strand MF, Wilson SR, Dembinski JL, Holsworth DD, Khvat A, Okun I, Petersen D, Krauss S (2011) A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model. PLoS One 6:e19904Google Scholar
  73. 73.
    Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Shibata S, Sato Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Miyamoto M, Tojo H, Baba A, Sasaki S (2012) Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors. Bioorg Med Chem 20:5496–5506Google Scholar
  74. 74.
    Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Tanaka Y, Shibata S, Sato Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Miyamoto M, Nishihara M, Ishimura Y, Tojo H, Baba A, Sasaki S (2012) Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and oral active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility. Bioorg Med Chem 20:5507–5517Google Scholar
  75. 75.
    Tojo H, Shibata S, Satoh Y, Kawamura M, Inazuka M, Yamakawa H, Kashiwagi M, Miyamoto M, Kondo S, Oohashi T, Oguro Y, Sasaki S (2011) TAK-441, a novel investigational small molecule hedgehog pathway inhibitor for use in cancer therapy. In: Proceedings of the 102nd annual meeting of the American Association for Cancer Research; 2011 Aprile 2–6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011, 71, Abstract number 2823Google Scholar
  76. 76.
    Kogame A, Tagawa Y, Shibata S, Tojo H, Miyamoto M, Tohyama K, Kondo T, Prakash S, Shyu WC, Asahi S (2013) Pharmacokinetic and pharmacodynamic modeling of Hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice. Durg Metab Disp 41:727–734Google Scholar
  77. 77.
    Li JJ, Shanmugasundaram V, Reddy S, Fleischer LL, Wang Z, Smith Y, Harter WG, Yue W-S, Swaroop M, Li L, Ji CX, Dettling D, Osak B, Fitzgerald LR, Conradi R (2010) Smoothened antagonists for hair inhibition. Bioorg Med Chem Lett 20:4932–4935Google Scholar
  78. 78.
    Beachy PA, Chen JK, Taipale AJN (2010) Modulators of Hedgehog signaling pathways, compositions and uses related thereto. US 069386 A1Google Scholar
  79. 79.
    Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT (2012) Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med Chem Lett 3:106–111Google Scholar
  80. 80.
    Jackson-Fisher AJ, McMahon MJ, Lam J, Li C, Engstrom LD, Tsaparikos K, Shields DJ, Fang DD, Lira ME, Zhu Z, Robbins MD, Schwab R, Munchhof MJ, VanArsdale T (2011) PF-04449913, a small molecule inhibitor of Hedgehog signaling, is effective in inhibiting tumor growth in preclinical models. In: Proceedings of the 102nd annual meeting of the American Association for Cancer Research; 2011 April 2–6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011, 71, Abstract number 4504Google Scholar
  81. 81.
    Rohner A, Spilker ME, Lam JL, Pascual B, Bartkowski D, Li QJ, Yang AH, Stevens G, Xu M, Wells PA, Planken S, Nair S, Sun S (2012) Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective smoothened antagonist that penetrates the blood–brain barrier. Mol Cancer Ther 11:57–65Google Scholar
  82. 82.
    Yang H, Xiang J, Wang N, Zhao Y, Hyman J, Li S, Jiang J, Chen JK, Yang Z, Lin S (2009) Converse conformational control of smoothened activity by structurally related small molecules. J Biol Chem 284:20876–20884Google Scholar
  83. 83.
    Wilson CW, Chen M-H, Chuang P-T (2009) Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PloS One 4:e5182Google Scholar
  84. 84.
    Rohatgi R, Milenkovic L, Corcoran RB, Scott MP (2009) Hedgehog signal transduction by smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci USA 106:3196–3201Google Scholar
  85. 85.
    Weierstall U, James D, Wang C, White TA, Wang D, Liu W, Spence JC, Bruce Doak R, Nelson G, Fromme P, Fromme R, Grotjohann I, Kupitz C, Zatsepin NA, Liu H, Basu S, Wacker D, Han GW, Katritch V, Boutet S, Messerschmidt M, Williams GJ, Koglin JE, Marvin Seibert M, Klinker M, Gati C, Shoeman RL, Barty A, Chapman HN, Kirian RA, Beyerlein KR, Stevens RC, Li D, Shah ST, Howe N, Caffrey M, Cherezov V (2014) Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography. Nat Commun 5:3309–3309Google Scholar
  86. 86.
    Che C, Li S, Yang B, Xin S, Yu Z, Shao T, Tao C, Lin S, Yang Z (2012) Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors. Beilstein J Org Chem 8:841–849Google Scholar
  87. 87.
    Manetti F, Faure H, Roudaut H, Gorojankina T, Traiffort E, Schoenfelder A, Mann A, Solinas A, Taddei M, Ruat M (2010) Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as smoothened antagonists. Mol Pharmacol 78:658–665Google Scholar
  88. 88.
    Roudaut H, Traiffort E, Gorojankina T, Vincent L, Faure H, Schoenfelder A, Mann A, Manetti F, Solinas A, Taddei M, Ruat M (2011) Identification and mechanism of action of the acylguanidine MRT-83, a novel potent smoothened antagonist. Mol Pharmacol 79:453–460Google Scholar
  89. 89.
    Solinas A, Faure H, Roudaut H, Traiffort E, Schoenfelder A, Mann A, Manetti F, Taddei M, Ruat M (2012) Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity. J Med Chem 55:1559–1571Google Scholar
  90. 90.
    Lipinski RJ, Bushman W (2010) Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening. Toxicol In Vitro 24:1404–1409Google Scholar
  91. 91.
    Wang J, Lu J, Mook RA Jr, Zhang M, Zhao S, Barak LS, Freedman JH, Lyerly HK, Chen W (2012) The insecticide synergist piperonyl butoxide inhibits Hedgehog signaling: assessing chemical risks. Toxicol Sci 128:517–523Google Scholar
  92. 92.
    Wang J, Mook RA Jr, Lu J, Gooden DM, Ribeiro A, Guo A, Barak LS, Lyerly HK, Chen W (2012) Identification of a novel smoothened antagonist that potently suppresses Hedgehog signaling. Bioorg Med Chem 20:6751–6757Google Scholar
  93. 93.
    Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002) Small molecule modulation of smoothened activity. Proc Natl Acad Sci USA 99:14071–14076Google Scholar
  94. 94.
    Rominger CM, Bee W-LT, Copeland RA, Davenport EA, Gilmartin A, Gontarek R, Hornberger KR, Kallal LA, Lai Z, Lawrie K, Lu Q, McMillan L, Truong M, Tummino PJ, Turunen B, Will M, Zuercher WJ, Rominger DH (2009) Evidence for allosteric interactions of antagonist binding to the smoothened receptor. J Pharm Exp Ther 329:995–1005Google Scholar
  95. 95.
    Chen JK, Sinha S (2006) Purmorphamine activates the Hedgehog pathway by targeting smoothened. Nat Chem Biol 2:29–30Google Scholar
  96. 96.
    Buttner A, Seifert K, Cottin T, Sarli V, Tzagkaroulaki L, Scholz S, Giannis A (2009) Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the Hedgehog signaling pathway. Bioorg Med Chem 17:4943–4954Google Scholar
  97. 97.
    Zhao Y, Tong C, Jiang J (2007) Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450:252–258Google Scholar
  98. 98.
    Tao H, Jin Q, Koo D-I, Liao X, Englund NP, Wang Y, Ramamurthy A, Schultz PG, Dorsch M, Kelleher J, Wu X (2011) Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened. Chem Biol 18:432–437Google Scholar
  99. 99.
    Wang Y, Arvanites AC, Davidow L, Blanchard J, Lam K, Yoo JW, Coy S, Rubin LL, McMahon AP (2012) Selective identification of Hedgehog pathway antagonists by direct analysis of smoothened ciliary translocation. ACS Chem Biol 7:1040–1048Google Scholar
  100. 100.
    Hyman JM, Firestone AJ, Heine VM, Zhao Y, Ocasio CA, Han K, Sun M, Rack PG, Sinha S, Wu JJ, Solow-Cordero DE, Jiang J, Rowitch DH, Chen JK (2009) Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci USA 106:14132–14137Google Scholar
  101. 101.
    Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA (2010) Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17:388–399Google Scholar
  102. 102.
    Kim J, Lee JJ, Kim J, Gardner D, Beachy PA (2010) Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci USA 107:13432–13437Google Scholar
  103. 103.
    Beauchamp EM, Ringer L, Bulut G, Sajwan KPM, Hall MD, Lee Y-C, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A (2011) Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest 121:148–160Google Scholar
  104. 104.
    Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, Riggins GJ, Epstein EH Jr, Beachy PA, Rudin CM (2013) Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 23:23–34Google Scholar
  105. 105.
    Nedelcu D, Liu J, Xu Y, Jao C, Salic A (2013) Oxysterol binding to the extracellular domain of smoothened in Hedgehog signaling. Nat Chem Biol 9:557–564Google Scholar
  106. 106.
    Rana R, Carroll CE, Lee H-J, Bao J, Marada S, Grace CRR, Guibao CD, Ogden SK, Zheng JJ (2013) Structural insights into the role of the smoothened cysteine-rich domain in Hedgehog signalling. Nat Commun 4:2965Google Scholar
  107. 107.
    Wang Y, Davidow L, Arvanites AC, Blanchard J, Lam K, Xu K, Oza V, Yoo JW, Ng JMY, Curran T, Rubin LL, McMahon AP (2012) Glucocorticoid compounds modify smoothened localization and Hedgehog pathway activity. Chem Biol 19:972–982Google Scholar
  108. 108.
    Yang B, Hird AW, Russell DJ, Fauber BP, Dakin LA, Zheng X, Su Q, Godin R, Brassil P, Devereaux E, Janetka JW (2012) Discovery of novel Hedgehog antagonists from cell-based screening: isosteric modification of p38 bisamides as potent inhibitors of SMO. Bioorg Med Chem Lett 22:4907–4911Google Scholar
  109. 109.
    Xin M, Wen J, Tang F, Tu C, Shen H, Zhao X (2013) The discovery of novel N-(2-pyrimidinylamino)benzamide derivatives as potent Hedgehog signaling pathway inhibitors. Bioorg Med Chem Lett 23:6777–6783Google Scholar
  110. 110.
    Xin M, Wen J, Tang F, Tu C, Huang W, Shen H, Zhao X, Cheng L, Wang M, Zhang L (2014) Synthesis and evaluation of 4-(2-pyrimidinylamino)benzamides inhibitors of hedgehog signaling pathway. Bioorg Med Chem Lett 24:983–988Google Scholar
  111. 111.
    Xin M, Zhang L, Tang F, Tu C, Wen J, Zhao X, Liu Z, Cheng L, Shen H (2014) Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors. Bioorg Med Chem 22:1429–1440Google Scholar
  112. 112.
    Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Herlihy KM, Duffner JL, Taveras KM, Hyman JM, Lee SW, Koehler AN, Chen JK, Fox JL, Mandinova A, Schreiber SL (2009) A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 5:154–156Google Scholar
  113. 113.
    Peng LF, Stanton BZ, Maloof N, Wang X, Schreiber SL (2009) Syntheses of aminoalcohol-derivative macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog. Bioorg Med Chem Lett 19:6319–6325Google Scholar
  114. 114.
    Dockendorff C, Nagiec MM, Weiwer M, Buhrlage S, Ting A, Nag PP, Germain A, Kim H-J, Youngsaye W, Scherer C, Bennion M, Xue L, Stanton BZ, Lewis TA, MacPherson L, Palmer M, Foley MA, Perez JR, Schreiber SL (2012) Macrocyclic Hedgehog pathway inhibitors: optimization of cellular activity and mode of action studies. ACS Med Chem Lett 3:808–813Google Scholar
  115. 115.
    Schaefer GI, Perez JR, Duvall JR, Stanton BZ, Shamji AF, Schreiber SL (2013) Discovery of small-molecule modulators of the Sonic Hedgehog pathway. J Am Chem Soc 135:9675–9680Google Scholar
  116. 116.
    Narayan R, Bauer JO, Strohmann C, Antonchick AP, Waldmann H (2013) Catalytic enantioselective synthesis of functionalized tropanes reveals novel inhibitors of Hedgehog signaling. Angew Chem Int Ed 12892–12896Google Scholar
  117. 117.
    Arai MA, Tateno C, Hosoya T, Koyano T, Kowithayakorn T, Ishibashi M (2008) Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana. Bioorg Med Chem 16:9420–9424Google Scholar
  118. 118.
    Arai MA, Tateno C, Koyano T, Kowithayakorn T, Kawabe S, Ishibashi M (2011) New Hedgehog/GLI-signaling inhibitors from Adenium obesum. Org Biomol Chem 9:1133–1139Google Scholar
  119. 119.
    Rifai Y, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M (2011) Acoschimperoside P, 2′ acetate: a Hedgehog signaling inhibitory constituent from Vallaris glabra. J Nat Med 65:629–632Google Scholar
  120. 120.
    Lu Y, Lin H, Drenkhahn SK, Starkey NJE, Jackson GA, Folk W, Fritsche KL, Lubahn DB (2011) Inhibition of Hedgehog signaling by extract of Sutherlandia. In: Proceedings of the 102nd annual meeting of the American Association for Cancer Research; 2011 April 2–6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011, 71, Abstract number 4221Google Scholar
  121. 121.
    Rifai Y, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M (2010) Terpenoids and a flavonoid glycoside from Acacia pennata leaves as Hedgehog/GLI-mediated transcriptional inhibitors. J Nat Prod 73:995–997Google Scholar
  122. 122.
    Slusarz A, Shenouda NS, Sakla MS, Drenkhahn SK, Narula AS, MacDonald RS, Besch-Williford CL, Lubahn DB (2010) Common botanical compounds inhibit the Hedgehog signaling pathway in prostate cancer. Cancer Res 70:3382–3390Google Scholar
  123. 123.
    Hosoya T, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M (2008) Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. Chembiochem 9:1082–1092Google Scholar
  124. 124.
    Shintani A, Toume K, Rifai T, Arai MA, Ishibashi M (2010) A bisindole alkaloid with Hedgehog signal inhibitory activity from the Myxomycete Perichaena chrysosperma. J Nat Prod 73:1711–1713Google Scholar
  125. 125.
    Mahindroo N, Connelly MC, Punchihewa C, Kimura H, Smeltzer MP, Wu S, Fujii N (2009) Structure–activity relationships and cancer-cell selective toxicity of novel inhibitors of glioma-associated oncogene homologe 1 (Gli1) mediated transcription. J Med Chem 52:4277–4287Google Scholar
  126. 126.
    He B, Fujii N, You L, Xu Z, Jablons DM (2007) Targeting Gli proteins in human cancer by small molecules. WO 067814 A2Google Scholar
  127. 127.
    Mahindroo N, Connelly MC, Punchihewa C, Yang L, Yan B, Fujii N (2010) Amide conjugates of ketoprofen and indole as inhibitors of Gli1-mediated transcription in the Hedgehog pathway. Bioorg Med Chem 18:4801–4811Google Scholar
  128. 128.
    Lauth M, Bergstrom A, Shimokawa T, Toftgard R (2007) Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA 104:8455–8460Google Scholar
  129. 129.
    Hayakawa I, Agatsuma T, Furukawa H, Kurakata S, Naruto S (2002) Imidazopyridine derivatives. WO 034748 A1Google Scholar
  130. 130.
    Lee J, Wu X, Pasca di Magliano M, Peters EC, Wang Y, Hong J, Hebrok M, Ding S, Cho CY, Schultz PG (2007) A small-molecule antagonist of the Hedgehog signaling pathway. ChemBioChem 8:1916–1919Google Scholar
  131. 131.
    Cupido T, Rack PG, Firestone AJ, Hyman JM, Han K, Sinha S, Ocasio CA, Chen JK (2009) The imidazopyridine derivative JK184 reveals dual roles for microtubules in hedgehog signaling. Angew Chem Int Ed 48:2321–2324Google Scholar
  132. 132.
    Beachy PA, Chen JK, Taipale J (2005) Hedgehog pathway antagonists. WO 033288 A2Google Scholar
  133. 133.
    Firestone AJ, Weinger JS, Maldonado M, Barlan K, Langston LD, O’Donnell M, Gelfand VI, Kapoor TM, Chen JK (2012) Small-molecule inhibitors of the AAA + ATPase motor cytoplasmic dynein. Nature 484:125–129Google Scholar
  134. 134.
    Baxter AD, Boyd EA, Guicherit OM, Porter J, Price S, Rubin LE (2001) Small organic molecule regulators of cell proliferation. WO 01/74344 A2Google Scholar
  135. 135.
    King RW (2002) Roughing up smoothened: chemical modulators of Hedgehog signaling. J Biol 1:8Google Scholar
  136. 136.
    Brunton SA, Stibbard JHA, Rubin LL, Guicherit OM, Kruse LI, Price S, di Lucrezia R, MacKinnon CH, Avery A, Park I, Buxton D, Boyd EA (2009) Potent agonists of the Hedgehog signaling pathway. Bioorg Med Chem Lett 19:4308–4311Google Scholar
  137. 137.
    Seifert K, Buttner A, Rigol S, Eilert N, Wandel E, Giannis A (2012) Potent small molecule Hedgehog agonists induce VEGF expression in vitro. Bioorg Med Chem 20:6465–6481Google Scholar
  138. 138.
    Wu X, Ding S, Ding Q, Gray NS, Schultz PG (2002) A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J Am Chem Soc 124:14520–14521Google Scholar
  139. 139.
    Lee S-J, Lee H-K, Cho SY, Choi J-K, Shin HK, Kwak E-J, Cho M-R, Kim H-R, Kim S-R, Kim Y-M, Park K-J, Choi J-K (2008) Identification of osteogenic purmorphamine derivatives. Mol Cells 26:380–386Google Scholar
  140. 140.
    Chen S, Zhang Q, Wu X, Schultz PG, Ding S (2004) Dedifferentiation of lineage-committed cells by a small molecule. J Am Chem Soc 126:410–411Google Scholar
  141. 141.
    Chen W, Barak LS, Lyerly HK, Wang J, Bond MC, Mook RA Jr (2011) Glucocorticoid drugs as smoothened agonists. WO 109711 A1Google Scholar
  142. 142.
    Wang J, Lu J, Bond MC, Chen M, Ren X-R, Lyerly HK, Barak LS, Chen W (2010) Identification of select glucocorticoids as smoothened agonists: potential utility for regenerative medicine. Proc Natl Acad Sci USA 107:9323–9328Google Scholar
  143. 143.
    Nachtergaele S, Mydock LK, Krishnan K, Rammohan J, Schlesinger PH, Covey DF, Rohatgi R (2012) Oxysterols are allosteric activators of the oncoprotein smoothened. Nat Chem Biol 8:211–220Google Scholar
  144. 144.
    Montgomery SR, Nargizyan T, Meliton V, Nachtergaele S, Rohatgi R, Stappenbeck F, Jung ME, Johnson JS, Aghdasi B, Tian H, Weintraub G, Inoue H, Atti E, Tetradis S, Pereira RC, Hokugo A, Alobaidaan R, Tan Y, Hahn TJ, Wang JC, Parhami F (2014) A novel osteogenic oxysterol compound for therapeutic development to promote bone growth: activation of Hedgehog signaling and osteogenesis through smoothened binding. J Bone Miner Res 29:1872–1885Google Scholar
  145. 145.
    Parhami F, Jung ME, Stappenbeck F, Pierce WM, Taylor GK, Merten KE (2013) Novel oxysterol analogue, Oxy149, induces osteogenesis and Hedgehog signaling and inhibits adipogenesis. WO 169397 A1Google Scholar
  146. 146.
    Corman A, DeBerardinis AM, Hadden MK (2012) Structure–activity relationships for side chain oxysterol agonists of the Hedgehog signaling pathway. ACS Med Chem Lett 3:828–833Google Scholar
  147. 147.
    Gorojankina T, Hoch L, Faure H, Roudaut H, Traiffort E, Schoenfelder A, Girard N, Mann A, Manetti F, Solinas A, Petricci E, Taddei M, Ruat M (2013) Discovery, molecular and pharmacological characterization of GSA-10, a novel small molecule positive modulator of smoothened. Mol Pharmacol 83:1020–1029Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Fabrizio Manetti
    • 1
    Email author
  • Maurizio Taddei
    • 1
  • Elena Petricci
    • 1
  1. 1.Department of Biotechnology, Chemistry and PharmacyUniversity of SienaSienaItaly

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