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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
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
McMillan R, Matsui W (2012) Molecular pathways: the Hedgehog signaling pathway in cancer. Clin Cancer Res 18:4883–4888
Scales SJ, de Sauvage FJ (2009) Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30:303–312
Amakye D, Jagani Z, Dorsch M (2013) Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med 19:1410–1422
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 35:1317–1333
Peukert S, Miller-Moslin K (2010) Small-molecule inhibitors of the Hedgehog signaling pathway as cancer therapeutics. ChemMedChem 5:500–512
Tremblay MR, McGovern K, Read MA, Castro AC (2010) New developments in the discovery of small molecule Hedgehog pathway antagonists. Curr Opin Chem Biol 14:428–435
Mahindroo N, Punchihewa C, Fujii N (2009) Hedgehog-Gli signaling pathway inhibitors as anticancer agents. J Med Chem 52:3829–3845
Lin TL, Matsui W (2012) Hedgehog pathway as a drug target: smoothened inhibitors in development. OncoTargets Ther 5:47–58
Hadden MK (2014) Hedgehog pathway agonism: therapeutic potential and small-molecule development. ChemMedChem 9:27–37
Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol BioSyst 6:44–54
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 406:1005–1009
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 45:1678–1682
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 9:8459–8464
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 16:2764–2768
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 51:6646–6649
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 7:2725–2735
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 52:4400–4418
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 109:7859–7864
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 9:2328–2335
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 11:2824–2827
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 21:3608–3612
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 100:456–463
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:e232
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 131:2289–2297
Banerjee U, Ghosh M, Hadden MK (2012) Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors. Bioorg Med Chem Lett 22:1330–1334
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 22:4859–4863
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 4:590–595
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):3724–3736
Baxter AD, Boyd EA, Guicherit OM, Price S, Rubin LL (2001) Mediators of the Hedgehog signaling pathways, compositions and uses related thereto. WO 26644 A2
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 100:4616–4621
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 17:3378–3387
Rubin L, Giucherit OM, Price S, Boyd EA (2003) Mediators of Hedgehog signaling pathways, compositions and uses related thereto. WO 011219 A2
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 A1
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 19:5576–5581
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 20:6748–6753
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 361:1173–1178
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 52:862–866
Atwood SX, Chang AL, Oro AE (2012) Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol 199:193–197
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 326:572–574
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 71:435–444
Baxter AD, Boyd EA, Guicherit OM, Price S, Rubin LD (2001) Mediators of the Hedgehog signaling pathways, compositions and uses related thereto. WO 019800 A3
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 51:1108–1110
Thomas RJ, Pericot Mohr G, Minetto G, Bakker A, Ferruzzi P (2009) The hedgehog pathway antagonists and therapeutic thereof. WO 074300 A2
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-38
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–E44
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 19:4191–4195
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 1:10
Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev 16:2743–2748
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 21:4422–4428
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 21:4429–4435
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 21:5274–5282
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 21:5283–5288
Balkovec JM, Thieringer R, Waddell ST (2008) Triazole derivatives which are Smo antagonists. WO 130552 A1
Austin RJ, Kaizerman JA, Lucas BS, McMinn DL, Powers JP (2009) Phthalazine compounds, compositions and methods of use. WO 002469 A1
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 20:3618–3622
Kaizerman JA, Lucas BS, McMinn DL, Zamboni R (2009) Annelated pyridazines for the treatment of tumors driven by inappropriate Hedgehog signaling. WO 035568 A1
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 20:4607–4610
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 21:5206–5209
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 52:3954–3968
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 8:1261–1265
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 1:130–134
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 2:51ra70
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 22:6573–6576
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 19:328–331
Hipskind PA, Takakuwa T (2009) Disubstituted phthalazine Hedgehog pathway antagonists. WO 134574 A2
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 2819
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 497:338–343
http://www.lillyoncologypipeline.com/Pages/hedgehog-smo-antagonist.aspx. Accessed February 2014
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 A1
Rocconi RP, Samant L (2013) Methods and compositions for the treatment of ovarian cancer. WO 043255 A1
http://www.exelixis.com/pipeline/xl139. Accessed 26 February 2014
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:e19904
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 20:5496–5506
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 20:5507–5517
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 2823
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 41:727–734
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 20:4932–4935
Beachy PA, Chen JK, Taipale AJN (2010) Modulators of Hedgehog signaling pathways, compositions and uses related thereto. US 069386 A1
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 3:106–111
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 4504
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 11:57–65
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 284:20876–20884
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:e5182
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 106:3196–3201
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 5:3309–3309
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 8:841–849
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 78:658–665
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 79:453–460
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 55:1559–1571
Lipinski RJ, Bushman W (2010) Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening. Toxicol In Vitro 24:1404–1409
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 128:517–523
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 20:6751–6757
Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002) Small molecule modulation of smoothened activity. Proc Natl Acad Sci USA 99:14071–14076
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 329:995–1005
Chen JK, Sinha S (2006) Purmorphamine activates the Hedgehog pathway by targeting smoothened. Nat Chem Biol 2:29–30
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 17:4943–4954
Zhao Y, Tong C, Jiang J (2007) Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450:252–258
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 18:432–437
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 7:1040–1048
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 106:14132–14137
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 17:388–399
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 107:13432–13437
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 121:148–160
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 23:23–34
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 9:557–564
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 4:2965
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 19:972–982
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 22:4907–4911
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 23:6777–6783
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 24:983–988
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 22:1429–1440
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 5:154–156
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 19:6319–6325
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 3:808–813
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 135:9675–9680
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 12892–12896
Arai MA, Tateno C, Hosoya T, Koyano T, Kowithayakorn T, Ishibashi M (2008) Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana. Bioorg Med Chem 16:9420–9424
Arai MA, Tateno C, Koyano T, Kowithayakorn T, Kawabe S, Ishibashi M (2011) New Hedgehog/GLI-signaling inhibitors from Adenium obesum. Org Biomol Chem 9:1133–1139
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 65:629–632
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 4221
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 73:995–997
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 70:3382–3390
Hosoya T, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M (2008) Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. Chembiochem 9:1082–1092
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 73:1711–1713
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 52:4277–4287
He B, Fujii N, You L, Xu Z, Jablons DM (2007) Targeting Gli proteins in human cancer by small molecules. WO 067814 A2
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 18:4801–4811
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 104:8455–8460
Hayakawa I, Agatsuma T, Furukawa H, Kurakata S, Naruto S (2002) Imidazopyridine derivatives. WO 034748 A1
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 8:1916–1919
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 48:2321–2324
Beachy PA, Chen JK, Taipale J (2005) Hedgehog pathway antagonists. WO 033288 A2
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 484:125–129
Baxter AD, Boyd EA, Guicherit OM, Porter J, Price S, Rubin LE (2001) Small organic molecule regulators of cell proliferation. WO 01/74344 A2
King RW (2002) Roughing up smoothened: chemical modulators of Hedgehog signaling. J Biol 1:8
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 19:4308–4311
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 20:6465–6481
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 124:14520–14521
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 26:380–386
Chen S, Zhang Q, Wu X, Schultz PG, Ding S (2004) Dedifferentiation of lineage-committed cells by a small molecule. J Am Chem Soc 126:410–411
Chen W, Barak LS, Lyerly HK, Wang J, Bond MC, Mook RA Jr (2011) Glucocorticoid drugs as smoothened agonists. WO 109711 A1
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 107:9323–9328
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 8:211–220
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 29:1872–1885
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 A1
Corman A, DeBerardinis AM, Hadden MK (2012) Structure–activity relationships for side chain oxysterol agonists of the Hedgehog signaling pathway. ACS Med Chem Lett 3:828–833
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 83:1020–1029
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Manetti, F., Taddei, M., Petricci, E. (2014). Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design. In: Ruat, M. (eds) The Smoothened Receptor in Cancer and Regenerative Medicine. Topics in Medicinal Chemistry, vol 16. Springer, Cham. https://doi.org/10.1007/7355_2014_61
Download citation
DOI: https://doi.org/10.1007/7355_2014_61
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-19754-8
Online ISBN: 978-3-319-19755-5
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)