A New Class of Small Molecule Inhibitor of BMP Signaling

PLoS ONE

Volumn 8, Issue 4, 2013, Pages

  Sanvitale, Caroline E ^a   Kerr, Georgina ^a   Chaikuad, Apirat ^a   Ramel, Marie Christine ^b   Mohedas, Agustin H ^c   Reichert, Sabine ^b   Wang, You ^c   Triffitt, James T ^a   Cuny, Gregory D ^c,d   Yu, Paul B ^c   Hill, Caroline S ^b   Bullock, Alex N ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

^d UNIVERSITY OF HOUSTON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [6 AMINO 5 (3,4,5 TRIMETHOXYPHENYL)PYRIDIN 3 YL]PHENOL; ACTIVIN RECEPTOR LIKE KINASE 1; BONE MORPHOGENETIC PROTEIN; ENZYME INHIBITOR; K 02288; LDN 193189; PROTEIN INHIBITOR; SMAD PROTEIN; UNCLASSIFIED DRUG; 3-(6-AMINO-5-(3,4,5-TRIMETHOXYPHENYL)PYRIDIN-3-YL)PHENOL; 6 [4 (1 PIPERAZINYL)PHENYL] 3 (4 QUINOLINYL)PYRAZOLO[1,5 A]PYRIMIDINE; ACTIVIN RECEPTOR 1; ACVR1 PROTEIN, HUMAN; ALPHA-AMINOPYRIDINE; AMINOPYRIDINE DERIVATIVE; PHENOL DERIVATIVE; PROTEIN BINDING; PROTEIN KINASE INHIBITOR; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE;

ARTICLE; BINDING AFFINITY; BINDING SITE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG EFFECT; DRUG MECHANISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESPONSE; DRUG SCREENING; DRUG STRUCTURE; EMBRYO; IC 50; IN VITRO STUDY; NONHUMAN; PROTEIN DETERMINATION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; ZEBRA FISH; ANGIOGENESIS; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DRUG EFFECTS; HUMAN; METABOLISM; MORPHOGENESIS;

DANIO RERIO;

ACTIVIN RECEPTORS, TYPE I; AMINOPYRIDINES; ANIMALS; BODY PATTERNING; BONE MORPHOGENETIC PROTEINS; HUMANS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; NEOVASCULARIZATION, PHYSIOLOGIC; PHENOLS; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PYRAZOLES; PYRIMIDINES; SIGNAL TRANSDUCTION; SMAD PROTEINS; ZEBRAFISH;

EID: 84876994820     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0062721     Document Type: Article

References (49)

1. Shi Y, Massague J, (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113: 685-700.
2. Wu MY, Hill CS, (2009) Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell 16: 329-343.
3. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J, (1994) Mechanism of activation of the TGF-beta receptor. Nature 370: 341-347.
4. Schmierer B, Hill CS, (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8: 970-982.
5. Heldin CH, Miyazono K, ten Dijke P, (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465-471.
6. Hong CC, Yu PB, (2009) Applications of small molecule BMP inhibitors in physiology and disease. Cytokine Growth Factor Rev 20: 409-418.
7. Vogt J, Traynor R, Sapkota GP, (2011) The specificities of small molecule inhibitors of the TGFss and BMP pathways. Cell Signal 23: 1831-1842.
8. Inman GJ, Nicolas FJ, Callahan JF, Harling JD, Gaster LM, et al. (2002) SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62: 65-74.
9. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, et al. (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4: 33-41.
10. Hao J, Ho JN, Lewis JA, Karim KA, Daniels RN, et al. (2010) In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem Biol 5: 245-253.
11. Cuny GD, Yu PB, Laha JK, Xing X, Liu JF, et al. (2008) Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorg Med Chem Lett 18: 4388-4392.
12. Wang L, Trebicka E, Fu Y, Ellenbogen S, Hong CC, et al. (2012) The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm Bowel Dis 18: 112-9.
13. Steinbicker AU, Sachidanandan C, Vonner AJ, Yusuf RZ, Deng DY, et al. (2011) Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 117: 4915-4923.
14. Theurl I, Schroll A, Sonnweber T, Nairz M, Theurl M, et al. (2011) Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood 118: 4977-84.
15. Lee YC, Cheng CJ, Bilen MA, Lu JF, Satcher RL, et al. (2011) BMP4 promotes prostate tumor growth in bone through osteogenesis. Cancer Res 71: 5194-5203.
16. Shi S, Hoogaars WM, de Gorter DJ, van Heiningen SH, Lin HY, et al. (2011) BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model. Neurobiol Dis 41: 353-360.
17. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, et al. (2008) BMP type I receptor inhibition reduces heterotopic ossification. Nat Med 14: 1363-1369.
18. Derwall M, Malhotra R, Lai CS, Beppu Y, Aikawa E, et al. (2012) Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis. Arterioscler Thromb Vasc Biol 32: 613-622.
19. Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, et al. (2012) Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol 32: 299-307.
20. Akhurst RJ, Hata A, (2012) Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov 11: 790-811.
21. Kaplan FS, Glaser DL, Pignolo RJ, Shore EM, (2007) A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton. Expert Opin Biol Ther 7: 705-712.
22. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, et al. (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38: 525-527.
23. Shore EM, Kaplan FS, (2010) Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6: 518-527.
24. Niesen FH, Berglund H, Vedadi M, (2007) The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat Protoc 2: 2212-2221.
25. Vedadi M, Niesen FH, Allali-Hassani A, Fedorov OY, Finerty PJ Jr, et al. (2006) Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination. Proc Natl Acad Sci U S A 103: 15835-15840.
26. Fedorov O, Marsden B, Pogacic V, Rellos P, Muller S, et al. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A 104: 20523-20528.
27. Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, et al. (2012) Structure of the Bone Morphogenetic Protein Receptor ALK2 and Implications for Fibrodysplasia Ossificans Progressiva. J Biol Chem 287: 36990-36998.
28. Lavery K, Swain P, Falb D, Alaoui-Ismaili MH, (2008) BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. J Biol Chem 283: 20948-20958.
29. Wu MY, Ramel MC, Howell M, Hill CS, (2011) SNW1 is a critical regulator of spatial BMP activity, neural plate border formation, and neural crest specification in vertebrate embryos. PLoS Biol 9: e1000593.
30. Langdon YG, Mullins MC, (2011) Maternal and zygotic control of zebrafish dorsoventral axial patterning. Annu Rev Genet 45: 357-377.
31. Hilton S, Naud S, Caldwell JJ, Boxall K, Burns S, et al. (2010) Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2. Bioorg Med Chem 18: 707-718.
32. Cui JJ, Tran-Dube M, Shen H, Nambu M, Kung PP, et al. (2011) Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 54: 6342-6363.
33. Gandhi L, Janne PA, (2012) Crizotinib for ALK-rearranged non-small cell lung cancer: a new targeted therapy for a new target. Clin Cancer Res 18: 3737-3742.
34. Younis Y, Douelle F, Feng TS, Gonzalez Cabrera D, Le Manach C, et al. (2012) 3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. J Med Chem 55: 3479-3487.
35. Boergermann JH, Kopf J, Yu PB, Knaus P, (2010) Dorsomorphin and LDN-193189 inhibit BMP-mediated Smad, p38 and Akt signalling in C2C12 cells. Int J Biochem Cell Biol 42: 1802-1807.
36. Savitsky P, Bray J, Cooper CD, Marsden BD, Mahajan P, et al. (2010) High-throughput production of human proteins for crystallization: the SGC experience. J Struct Biol 172: 3-13.
37. Leslie AG, (2006) The integration of macromolecular diffraction data. Acta Crystallogr D Biol Crystallogr 62: 48-57.
38. Evans P, (2006) Scaling and assessment of data quality. Acta Crystallogr D Biol Crystallogr 62: 72-82.
39. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, et al. (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658-674.
40. Emsley P, Cowtan K, (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126-2132.
41. Murshudov GN, Vagin AA, Dodson EJ, (1997) Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53: 240-255.
42. Painter J, Merritt EA, (2006) Optimal description of a protein structure in terms of multiple groups undergoing TLS motion. Acta Crystallogr D Biol Crystallogr 62: 439-450.
43. Davis IW, Leaver-Fay A, Chen VB, Block JN, Kapral GJ, et al. (2007) MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res 35: W375-383.
44. Korchynskyi O, ten Dijke P, (2002) Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277: 4883-4891.
45. Westerfield M (2000) The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). Eugene (Oregon): University of Oregon Press.
46. Lawson ND, Weinstein BM, (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248: 307-318.
47. Cannon JE, Upton PD, Smith JC, Morrell NW, (2010) Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists. Br J Pharmacol 161: 140-149.
48. Dorey K, Hill CS, (2006) A novel Cripto-related protein reveals an essential role for EGF-CFCs in Nodal signalling in Xenopus embryos. Dev Biol 292: 303-316.
49. Kishimoto Y, Lee KH, Zon L, Hammerschmidt M, Schulte-Merker S, (1997) The molecular nature of zebrafish swirl: BMP2 function is essential during early dorsoventral patterning. Development 124: 4457-4466.