Novel bone-targeted Src tyrosine kinase inhibitor drug discovery

Current Opinion in Drug Discovery and Development

Volumn 6, Issue 5, 2003, Pages 729-741

  Shakespeare, William C ^a   Metcalf III, Chester A ^a   Wang, Yihan ^a   Sundaramoorthi, Raji ^a   Keenan, Terence ^a   Weigele, Manfred ^a   Bohacek, Regine S ^a   Dalgarno, David C ^a   Sawyer, Tomi K ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

Antiresorptive; Bisphosphonate; Bone targeting; Osteodast; Src tyrosine kinase

Indexed keywords

2,3 DIHYDRO 2 OXO 3 (4,5,6,7 TETRAHYDRO 1H INDOL 2 YLMETHYLENE) 1H INDOLE 5 SULFONIC ACID DIMETHYLAMIDE; 4 AMINO 7 TERT BUTYL 5 (4 METHYLPHENYL)PYRAZOLO[3,4 D]PYRIMIDINE; ADENOSINE PHOSPHATE; ADENOSINE TRIPHOSPHATE; ALENDRONIC ACID; ANTINEOPLASTIC AGENT; AP 21526; AP 21733; AP 21773; AP 21827; AP 21909; AP 22059; AP 22110; AP 22408; AP 22409; AP 22650; AP 23236; BENZENE DERIVATIVE; BISPHOSPHONIC ACID DERIVATIVE; CALCIUM CARBONATE; CARBOXYLIC ACID DERIVATIVE; CGP 77675; CITRIC ACID; FUNCTIONAL GROUP; METHOTREXATE; NVP AAK980; PD 161570; PHOSPHINIC ACID DERIVATIVE; PHOSPHONIC ACID DERIVATIVE; PHOSPHOTYROSINE; PHTHALIC ACID DIMETHYL ESTER; PROSTAGLANDIN E2; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; TETRACYCLINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZOLEDRONIC ACID;

BONE; BONE DISEASE; BONE METASTASIS; CATALYSIS; CHELATION; DRUG DESIGN; DRUG EFFICACY; DRUG TARGETING; ENZYME ACTIVITY; MOLECULAR RECOGNITION; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; PRECIPITATION; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; BONE AND BONES; BONE NEOPLASMS; BONE RESORPTION; DIPHOSPHONATES; DRUG DESIGN; HUMANS; MODELS, MOLECULAR; OSTEOCLASTS; OSTEOPOROSIS; PHENOLS; PROTEIN CONFORMATION; PURINES; SRC HOMOLOGY DOMAINS; SRC-FAMILY KINASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0142123142     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (65)

1. Francis MD, Russel RGG, Fleisch H: Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science (1969) 165(899):1264-1266.
2. Fleisch H: Bisphosphonates: Mechanisms of action. Exp Opin Ther Pat (2001) 11(9):1371-1381. A review of conventional bisphosphonate drugs, including pharmacokinetics and SARs.
3. Geddes AD, D'Souaza SM, Ebetino FH, Ibbotson KJ: Bisphosphonates: Structure-activity relationships and therapeutic implications. J Bone Miner Res (1994) 8:265-306.
4. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC: Cellular and molecular mechanisms of action of bisphosphonates. Cancer (2000) 88(12 Suppl):2961-2978. A comprehensive review on the mechanisms of action of bisphosphonate drugs.
5. Teitelbaum SL: Bone resorption by osteoclasts. Science (2000) 289(5484):1504-1508.
6. Ducy P, Schinke T, Karsenty G: The osteoblast: A sophisticated fibroblast under central surveillance. Science (2000) 289(5484):1501-1504.
7. Uludag H: Bisphosphonates as a foundation of drug delivery to bone. Curr Pharm Design (2002) 8(21):1929-1944. An excellent review of bone-targeting as a basis for delivering pharmaceutical agents to the bone that mainly highlights bisphosphonates, although other heterocycles are described.
8. Fleisch H: Bisphosphonates in Bone Disease. From the Laboratory to the Patient. Academic Press Inc, San Diego, CA, USA (2000).
9. Sims N, Baron R: Bone cells and their functions. in: Skeletal Growth Factors. Canalis E (Ed), Lippincott Williams & Wilkins, Philadelphia, PA, USA (2000):1-16.
10. 14C]citric acid. Calcif Tissue Int (1993) 52(5):372-377.
11. Wilson TM, Charifson PS, Baxter AD, Geddie NG: Bone-targeted drugs. 1. Identification of heterocycles with hydroxyapatite affinity. Bioorg Med Chem Lett (1996) 6(9):1043-1046.
12. Meyers HM: Structure-activity relationships (SAR) of hydroxyapatite-binding molecules. Calcif Tissue Int (1987) 40:344-348.
13. Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, Golub E, Rodan GA: Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest (1991) 88(6):2095-2105.
14. Lin JH: Bisphosphonates: A review of their pharmacokinetic properties. Bone (1996) 18(2):75-85.
15. Murphy CAD, Meledez-Alafort L, Montaya-Molina C, Sepulveda-Mendez J: Technetium-99m-alendronate: A new radiopharmaceutical for bone scanning. Arch Med Res (1996) 27:481-482.
16. Sturtz G, Appere G, Breistol K, Fodstad O, Schwartsmann G, Hendricks HR: A study of the delivery-targeting concept applied to antineoplastic drugs active on human osteosarcoma. I. Synthesis and biological activity in nude mice carrying human osteosarcoma xenografts of gem-bisphosphonic methotrexate analogs. Eur J Med Chem (1992) 27:825-833.
17. 2-bisphosphonate conjugates: Potential agents for treatment of osteoporosis. Bioorg Med Chem (1999) 7(5):901-919.
18. Shakespeare W, Yang M, Bohacek R, Cerasoli F, Stebbins K, Sundaramoorthi R, Azimiora M, Vu C, Pradeepan S, Metcalf C III, Haraldson C et al: Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity. Proc Natl Acad Sci USA (2000) 97(17):9373-9378.
19. Brugge JS, Erikson RL: Identification of a transformation-specific antigen induced by an avian sarcoma virus. Nature (1977) 269(5626):346-348.
20. Collet MS, Erikson RL: Protein kinase activity associated with avian sarcoma virus src gene product. Proc Natl Acad Sci USA (1978) 75(4):2021-2024.
21. Levinson AD, Oppermann H, Levintow L, Varmus HE, Bishop JM: Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. Cell (1978) 15(2):561-572.
22. Paul R, Zhang ZG, Eliceiri BP, Jiang Q, Boccia AD, Zhang RL, Chopp M, Cheresh DA: Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med (2001) 7(2):222-227.
23. Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG, Frame MC: Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol (2002) 4(8):632-638.
24. Soriano P, Montgomery C, Geske R, Bradley A: Targeted disruption of the c-src proto-oncogene leads to osteoporosis in mice. Cell (1991) 64(4):693-702.
25. Marzia M, Sims NA, Voit S, Migliaccio S, Taranta A, Bernardini S, Faraggiana T, Yoneda T, Mundy GR, Boyce BF, Baron R et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol (2000) 151(2):311-320.
26. Amling M, Neff L, Priemel M, Schilling AF, Rueger JM, Baron R: Progressive increase in bone mass and development of odontomas in aging osteopetrotic c-src-deficient mice. Bone (2000) 27(5):603-610.
27. Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR: Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest (1992) 90(4):1622-1627.
28. Schwartzberg PL, Xing L, Hoffmann O, Lowell CA, Garrett L, Boyce BF, Varmus HE: Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice. Genes Dev (1997) 11(21):2835-2844.
29. Thomas SM, Brugge JS: Cellular functions regulated by Src family kinases. Ann Rev Cell Dev Biol (1997) 13:513-609.
30. Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG et al: SH2 domains recognize specific phosphopeptide sequences. Cell (1993) 72(5):767-778.
31. Xu W, Harrison SC, Eck MJ: Three dimensional structure of the tyrosine kinase c-Src. Nature (1997) 385(6617):595-602.
32. Xu W, Doshi A, Lei M, Eck MJ, Harrison SC: Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell (1999) 3(5):629-638.
33. Sicheri F, Moarefi I, Kuriyan J: Crystal structure of the Src family tyrosine kinase Hck. Nature (1997) 385(6617):602-609.
34. Schindler T, Sicheri F, Pico A, Gazit A, Levitzki A, Kuriyan J: Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol Cell (1999) 3(5):639-648.
35. Yamaguchi H, Hendrickson WA: Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature (1996) 384(6608):484-489.
36. Sawyer TK, Bohacek RS, Dalgarno DC, Eyermann CJ, Kawahata N, Metcalf III CA, Shakespeare WC, Sundaramcorthi R, Wang Y, Yang MG: Src homology-2 inhibitors: Peptidomimetic and nonpeptide. Mini Rev Med Chem (2002) 8:2049-2075.
37. Shakespeare WC: SH2 domain inhibition: A problem solved? Curr Opin Chem Biol (2001) 5(4):409-415.
38. Bohacek RS, Dalgamo DC, Hatada M, Jacobsen VA, Lynch BA, Macek KJ, Merry T, Metcalf CA III, Narula SS, Sawyer TK, Shakespeare WC et al: X-ray structure of citrate bound to Src SH2 leads to a high-affinity, bone-targeted Src SH2 inhibitor. J Med Chem (2001) 44(5):660-663.
39. Src SH2 domain. Bioorg Med Chem Lett (2001) 11(17):2319-2323.
40. Waksman G, Kominos D, Robertson SC, Pant N, Baltimore D, Birge RB, Cowburn D, Hanafusa H, Mayer BJ, Overduin M, Resh MD et al: Crystal structure of the phosphotyrosine recognition domain (SH2) of the v-src tyrosine kinase complexed with tyrosine-phosphorylated peptides. Nature (1992) 358(6388):646-653.
41. Waksman G, Shoelson SE, Pant N, Cowburn D, Kuriyan J: Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: Crystal structures of the complexed and peptide-free forms. Cell (1993) 72(5):779-790.
42. Src SH2 domain. J Am Chem Soc (1997) 119:12471-12476. A novel benzamide template, which was the foundation for more potent, second-generation Src SH2 inhibitors, is described.
43. Violette SM, Guan W, Bartlett C, Smith JA, Bardelay C, Antoine E, Rickles RJ, Mandine E, van Schravendijk MR, Adams SE, Lynch BA et al. Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption. Bone (2001) 28(1):54-64.
44. von Stechow D, Alexander JM, Fish S, Chorev M, Mueller R, Rosenblatt M, Iuliucci J, Wang Y, Metcalf C, Keenan T, Sundaramoorthi R et al: Novel Src tyrosine kinase inhibitors prevent ovariectomy-induced bone loss in a Swiss-Webster Mouse model of post-menapausal osteoporosis. American Society for Bone and Mineral Research, 22nd Meeting, Toronto, Canada (2000).
45. Hamby JM, Connolly CJC, Schroeder MC, Winters RT, Showalter HDH, Panek RL, Major TC, Olsewski B, Ryan MJ, Dahring T, Lu GH et al: Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem (1997) 40(15):2296-2303.
46. Klutchko SR, Hamby JM, Boschelli DH, Wu Z, Kraker AJ, Amar AM, Hartl BG, Shen C, Klohs WD, Steinkampf RW, Driscoll DL et al: 2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones. Structure-activity relationships against selected tyrosine kinase inhibitors and in vitro and in vivo anticancer activity. J Med Chem (1998) 41(17):3276-3292.
47. Boschelli DH, Wu Z, Klutchko SR, Schowalter HDH, Hamby JM, Lu GH, Major TC, Dahring TK, Batley B, Panek RL, Keiser J et al: Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d]pyrimidines: Identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem (1998) 41(22):4365-4377.
48. Missbach M, Jeschke M, Feyen J, Müller K, Glatt M, Green J, Susa M: A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo. Bone (1999) 24(5):437-449. The first description of a small-molecule, ATP-competitive inhibitor of STK with demonstrated in vivo antiresorptive activity.
49. Altmann E, Widler L, Missbach M: N7-Substituted-5-aryl-pyrrolo[2,3-d]pyrimidines represent a versatile class of potent inhibitors of the tyrosine kinase c-Src. Mini Rev Med Chem (2002) 2(3):201-208.
50. Missbach M, Attmann E, Susa M: Tyrosine kinase inhibition in bone metabolism. Curr Opin Drug Discovery Dev (2000) 3(5):541-548.
51. Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA: Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem (1996) 271(2):695-701.
52. Wang YD, Miller K, Boschelli DH, Ye F, Wu B, Floyd MB, Powell DW, Wissner A, Weber JM, Boschelli F: Inhibitors of Src tyrosine kinase: The preparation and structure-activity relationship of 4-anilino-3-cyanoquinolines and 4-anilinoquinazolines. Bioorg Med Chem Lett (2000) 10(21):2477-2480.
53. Boschelli DH, Ye F, Wang YD, Dutia M, Johnson SL, Wu B, Miller K, Powell DW, Yaczko D, Young M, Tischler M et al:. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem (2001) 44(23):3965-3977.
54. Blake RA, Broome MA, Liu X, Wu J, Gishizky M, Sun L, Courtneidge SA: SU6656, a selective Src family kinase inhibitor, used to probe growth factor signaling. Mol Cell Biol (2000) 20(23):9018-9027.
55. Zimmerman J, Buchdunger E, Mett H, Meyer T, Lydon NB: Potent and selective inhibitors of the Abl-kinase: Phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett (1997) 7(2):187-192.
56. Gamse R, Wilder L, Missbach M, Buhl T, Kneissel M, Beerli R, Susa S: NVP-AAK980, a novel 6-phenylamino-2-alkylamino-purine derivative, potently inhibits the tyrosine kinase Src and bone resorption. J Bone Miner Res (1999) 14(Suppl 1):487.
57. Yoneda T, Lowe C, Lee CH, Gutierrez G, Niewolna M, Williams PJ, Izbicka E, Uehara Y, Mundy GR: Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo. J Clin Invest (1993) 91(6):2791-2795.
58. Hubbard SR: Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J (1997) 16(18):5572-5581.
59. Gray NS, Wodicka L, Thunissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim S-H et al: Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science (1998) 281(5376):533-538.
60. Vu CB, Luke GP, Kawahata N, William CS, Wang Y, Sundaramoorthi R, Metcalf III, CA, Keenan TP, Pradeepan S, Corpuz E, Merry T et al: Bone-targeted pyrido[2,3-dipyrimidin-7-ones: Potent inhibitors of Src tyrosine kinase as novel antiresorptive agents. Bioorg Med Chem Lett (2003) 13(18):3071-3074.
61. Sundaramoorthi R, William CS, Keenan TP, Metcalf III CA, Wang Y, Mani U, Liu S, Bohacek RS, Narula SS, Dalgarno DC, Schranvendijk MR et al: Bone-targeted Src kinase inhibitors: Novel pyrrolo- and pyrazolopyrimidine analogs. Bioorg Med Chem Lett (2003) 13(18):3063-3066.
62. Wang Y, Metcalf III CA, William CS, Sundaramoorthi R, Keenan TP, Bohacek RS, van Schranvendijk MR, Violette SM, Narula SS, Dalgarno DC, Haraldson C et al. Bone-targeted 2,6,9-trisubstituted purines: Novel inhibitors of Src tyrosine kinase for the treatment of bone diseases. Bioorg Med Chem Lett (2003) 13(18):3067-3070.
63. Metcalf III CA, Bohacek RS, Wang Y, Sundammoorthi R, Vu CB, Luke GP, William CS, Keenan TP, Haraldson C, Roses J, Dalgarno DC et al: AP23236, a potent, selective inhibitor of Src tyrosine kinase possessing antiresorptive activity in vivo. (2003): manuscript in preparation.
64. Shakespeare W, Wang Y, Metcalf C, Sundaramoorthi R, Keenan T, Bohacek R, van Schravendijk MR, Snodgrass J, Dilauro A, Roeloffzen S, Liu S et al: Development of a novel bone-targeted Src tyrosine kinase inhibitor AP23451 having potent activity in an animal model of osteolytic bone metastasis. Proc Am Assoc Cancer Res (2003) 44:Abs 3971.
65. Poirier VJ, Huelsmeyer MK, Kurzman ID, Thamm DH, Vail DM: The bisphosphonates alendronate and zoledronate are inhibitors of human and canine osteosarcoma cell growth in vitro. Proc Am Assoc Cancer Res (2003) 44:Abs 1711.