Hck inhibitors as potential therapeutic agents in cancer and HIV infection

Current Medicinal Chemistry

Volumn 22, Issue 13, 2015, Pages 1540-1564

  Musumeci, F ^a   Schenone, S ^a   Brullo, C ^a   Desogus, A ^a   Botta, L ^b   Tintori, C ^b  

^a UNIVERSITY OF GENOA   (Italy)

^b UNIVERSITY OF SIENA   (Italy)

Author keywords

AIDS; Cancer; Hck; HIV; Inhibitor; Nef; Tyrosine kinase

Indexed keywords

6 (4 FLUOROPHENYL) 2,3 DIHYDRO 5 (4 PYRIDYL)IMIDAZO[2,1 B]THIAZOLE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTILEUKEMIC AGENT; AP 23846; BMS 279700; BOSUTINIB; DASATINIB; HEMATOPOIETIC CELL KINASE; HEMATOPOIETIC CELL KINASE INHIBITOR; IMATINIB; NEGATIVE REGULATORY FACTOR; PG 1009247; PROTEIN TYROSINE KINASE INHIBITOR; PYRAZOLO[3,4 D]PYRIMIDINE DERIVATIVE; PYRROLO[2,3 D]PYRIMIDINE DERIVATIVE; SARACATINIB; UNCLASSIFIED DRUG; VIRUS PROTEIN; PROTEIN KINASE INHIBITOR;

ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; ALPHA HELIX; AMINO TERMINAL SEQUENCE; ANTIPROLIFERATIVE ACTIVITY; ANTIVIRAL ACTIVITY; ARTICLE; AUTOPHOSPHORYLATION; BIOLOGICAL ACTIVITY; CARBOXY TERMINAL SEQUENCE; CHRONIC MYELOID LEUKEMIA; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; ENZYME STRUCTURE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 2; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LARGE CELL LYMPHOMA; LEUKEMIA; LYMPHATIC LEUKEMIA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN DEPHOSPHORYLATION; PROTEIN DNA INTERACTION; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; VIRUS REPLICATION; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DEVELOPMENT; ENZYMOLOGY; HIV INFECTIONS; METABOLISM; NEOPLASMS;

ANIMALS; DRUG DISCOVERY; HIV INFECTIONS; HUMANS; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-HCK;

EID: 84931292011     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867322666150209152057     Document Type: Article

References (173)

1. Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science, 2002, 298, 1912-1934.
2. Kim, L.C.; Song, L.; Haura, E.B. Src kinases as therapeutic targets for cancer. Nat. Rev. Clin. Oncol., 2009, 6, 587-595.
3. Thomas, S.M.; Brugge, J.S. Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol., 1997, 13, 513-609.
4. Lichtenberg, U.; Quintrell, N.; Bishop, J.M. Human proteintyrosine kinase gene HCK: expression and structural analysis of the promoter region. Oncogene, 1992, 7, 849-858.
5. Cohen, J. The immunopathogenesis of sepsis. Nature, 2002, 420, 885-891.
6. Suen, P.W.; Ilic, D.; Caveggion, E.; Berton, G.; Damsky, C.H.; Lowell, C.A. Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages. J. Cell. Sci., 1999, 112, 4067-4078.
7. Guiet, R.; Poincloux, R.; Castandet, J.; Marois, L.; Labrousse, A.; Le Cabec, V.; Maridonneau-Parini, I. Hematopoietic cell kinase (Hck) isoforms and phagocyte duties-from signaling and actin reorganization to migration and phagocytosis. Eur. J. Cell. Biol., 2008, 87, 527-542.
8. Pene-Dumitrescu, T.; Smithgall, T.E. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J. Biol. Chem., 2010, 285, 21446-21457.
9. Emert-Sedlak, L.A.; Narute, P.; Shu, S.T.; Poe, J.A.; Shi, H.; Yanamala, N.; Alvarado. J.J.; Lazo, J.S.; Yeh, J.I.; Johnston, P.A.; Smithgall, T.E. Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. Chem. Biol., 2013, 20, 82-91.
10. Quintrell, N.; Lebo, R.; Varmus, H.; Bishop, J.M.; Pettenati, M.J.; Le Beau, M.M.; Diaz, M.O.; Rowley, J.D. Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Mol. Cell. Biol., 1987, 7, 2267-2275.
11. Ziegler, S.F.; Marth, J.D.; Lewis, D.B.; Perlmutter, R.M. Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. Mol. Cell. Biol., 1987, 7, 2276-2285.
12. Sicheri, F.; Moarefi, I.; Kuriyan, J. Crystal structure of the Src family tyrosine kinase Hck. Nature, 1997, 385, 602-609.
13. Silverman, L.; Sudol, M.; Resh, M.D. Members of the src family of nonreceptor tyrosine kinases share a common mechanism for membrane binding. Cell Growth Differ., 1993, 4, 475-482.
14. Robbins, S.M.; Quintrell, N.A.; Bishop, J.M. Myristoylation and differential palmitoylation of the HCK protein-tyrosine kinases govern their attachment to membranes and association with caveolae. Mol. Cell. Biol., 1995, 15, 3507-3515.
15. Roskoski, R. Jr. Src protein-tyrosine kinase structure and regulation. Biochem. Biophys. Res. Commun., 2004, 324, 1155-1164.
16. Boggon, T.J.; Eck, M.J. Structure and regulation of Src family kinases. Oncogene, 2004, 23, 7918-7927.
17. Okada, M. Regulation of the SRC family kinases by Csk. Int. J. Biol. Sci., 2012, 8, 1385-1397.
18. Sicheri, F.; Kuriyan, J. Structures of Src-family tyrosine kinases. Curr. Opin. Struct. Biol., 1997, 7, 777-785.
19. Young, M.A.; Gonfloni, S.; Superti-Furga, G.; Roux, B.; Kuriyan, J. Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation. Cell, 2001, 105, 115-126.
20. Engen, J.R.; Wales, T.E.; Hochrein, J.M.; Meyn, M.A. 3rd, Banu Ozkan, S.; Bahar, I.; Smithgall, T.E. Structure and dynamic regulation of Src-family kinases. Cell Mol. Life Sci., 2008, 65, 3058-3073.
21. Alvarado, J.J.; Betts, L.; Moroco, J.A.; Smithgall, T.E.; Yeh, J.I. Crystal structure of the Src family kinase Hck SH3-SH2 linker regulatory region supports an SH3-dominant activation mechanism. J. Biol. Chem., 2010, 285, 35455-35461.
22. Lock, P.; Ralph, S.; Stanley, E.; Boulet, I.; Ramsay, R.; Dunn, A.R. Two isoforms of murine hck, generated by utilization of alternative translational initiation codons, exhibit different patterns of subcellular localization. Mol. Cell. Biol., 1991, 11, 4363-4370.
23. Möhn, H.; Le Cabec, V.; Fischer, S.; Maridonneau-Parini, I. The src-family protein-tyrosine kinase p59hck is located on the secretory granules in human neutrophils and translocates towards the phagosome during cell activation. Biochem. J., 1995, 309, 657-665.
24. Carréno, S.; Gouze, M.E.; Schaak, S.; Emorine, L.J.; Maridonneau-Parini, I. Lack of palmitoylation redirects p59Hck from the plasma membrane to p61Hck-positive lysosomes. J. Biol. Chem., 2000, 275, 36223-36229.
25. Cougoule, C.; Carreno, S.; Castandet, J.; Labrousse, A.; Astarie-Dequeker, C.; Poincloux, R.; Le Cabec, V.; Maridonneau-Parini, I. Activation of the lysosome-associated p61Hck isoform triggers the biogenesis of podosomes. Traffic, 2005, 6, 682-694.
26. Carreno, S.; Caron, E.; Cougoule, C.; Emorine, L.J.; Maridonneau-Parini, I. P59Hck isoform induces F-actin reorganization to form protrusions of the plasma membrane in a Cdc42-and Racdependent manner. J. Biol. Chem., 2002, 277, 21007-21016.
27. Willman, C.L.; Stewart, C.C.; Longacre, T.L.; Head, D.R.; Habbersett, R.; Ziegler, S.F.; Perlmutter, R.M. Expression of the c-fgr and hck protein-tyrosine kinases in acute myeloid leukemic blasts is associated with early commitment and differentiation events in the monocytic and granulocytic lineages. Blood, 1991, 77, 726-734.
28. Ziegler, S.F.; Wilson, C.B.; Perlmutter, R.M. Augmented expression of a myeloid-specific protein tyrosine kinase gene (hck) after macrophage activation. J. Exp. Med., 1988, 168, 1801-1810.
29. English, B.K.; Orlicek, S.L.; Mei, Z.; Meals, E.A. Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in macrophages: evidence for involvement of the hck tyrosine kinase. J. Leukoc. Biol., 1997, 62, 859-864.
30. Marks, D.C.; Csar, X.F.; Wilson, N.J.; Novak, U.; Ward, A.C.; Kanagasundarum, V.; Hoffmann, B.W.; Hamilton, J.A. Expression of a Y559F mutant CSF-1 receptor in M1 myeloid cells: A role for Src kinases in CSF-1 receptor-mediated differentiation. Mol. Cell Biol. Res. Commun., 1999, 1, 144-152.
31. Kloog, Y.; Mor, A. Cytotoxic-T-lymphocyte antigen 4 receptor signaling for lymphocyte adhesion is mediated by C3G and Rap1. Mol. Cell. Biol., 2014, 34, 978-988.
32. Asai, T.; Morrison, S.L. The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model. J. Biol. Chem., 2013, 288, 10395-10405.
33. Page, T.H.; Smolinska, M.; Gillespie, J.; Urbaniak, A.M.; Foxwell, B.M. Tyrosine kinases and inflammatory signalling. Curr. Mol. Med., 2009, 9, 69-85.
34. Smolinska, M.J.; Page, T.H.; Urbaniak, A.M.; Mutch, B.E.; Horwood, N.J. Hck tyrosine kinase regulates TLR4-induced TNF and IL-6 production via AP-1. J. Immunol., 2011, 187, 6043-6051.
35. Gong, J.; Yan, J.C.; Gu, H.Y.; Kong, X.Q.; Cao, K.J. Expressing murine p56Hck(ca) promotes HeLa cells' motility and invasion via triggering redistribution of F-actin and microtubules. Mol. Biol. Rep., 2012, 39, 6521-6527.
36. Park, H.; Dovas, A.; Hanna, S.; Lastrucci, C.; Cougoule, C.; Guiet, R.; Maridonneau-Parini, I.; Cox, D. Tyrosine phosphorylation of Wiskott-Aldrich syndrome protein (WASP) by Hck regulates macrophage function. J. Biol. Chem., 2014, 289, 7897-7906.
37. Miyazaki, T.; Sanjay, A.; Neff, L.; Tanaka, S.; Horne, W.C.; Baron, R. Src kinase activity is essential for osteoclast function. J. Biol. Chem., 2004, 279, 17660-17666.
38. Vérollet, C.; Gallois, A.; Dacquin, R.; Lastrucci, C.; Pandruvada, S.N.; Ortega, N.; Poincloux, R.; Behar, A.; Cougoule, C.; Lowell, C.; Al Saati, T.; Jurdic, P.; Maridonneau-Parini, I. Hck contributes to bone homeostasis by controlling the recruitment of osteoclast precursors. FASEB J., 2013, 27, 3608-3618.
39. Deininger, M.W.; Goldman, J.M.; Melo, J.V. The molecular biology of chronic myeloid leukemia. Blood, 2000, 96, 3343-3356.
40. Hantschel, O.; Superti-Furga, G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat. Rev. Mol. Cell. Biol., 2004, 5, 33-44.
41. Kantarjian, H.; Shah, N.P.; Hochhaus, A.; Cortes, J.; Shah, S.; Ayala, M.; Moiraghi, B.; Shen, Z.; Mayer, J.; Pasquini, R.; Nakamae, H.; Huguet, F.; Boqué, C.; Chuah, C.; Bleickardt, E.; Bradley-Garelik, M.B.; Zhu, C.; Szatrowski, T.; Shapiro, D.; Baccarani, M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med., 2010, 362, 2260-2270.
42. Schenone, S.; Brullo, C.; Botta, M. New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms. Curr. Med. Chem., 2010, 17, 1220-1245.
43. Danhauser-Riedl, S.; Warmuth, M.; Druker, B.J.; Emmerich, B.; Hallek, M. Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res., 1996, 56, 3589-3596.
44. Warmuth, M.; Bergmann, M.; Priess, A.; Häuslmann, K.; Emmerich, B.; Hallek, M. The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J. Biol. Chem., 1997, 272, 33260-33270.
45. Stephen, A.G.; Esposito, D.; Bagni, R.K.; McCormick, F. Dragging Ras back in the ring. Cancer Cell., 2014, 25, 272-281.
46. Stanglmaier, M.; Warmuth, M.; Kleinlein, I.; Reis, S.; Hallek, M. The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains. Leukemia, 2003, 17, 283-289.
47. Meyn, M.A. 3rd; Wilson, M.B.; Abdi, F.A.; Fahey, N.; Schiavone, A.P.; Wu, J.; Hochrein, J.M.; Engen, J.R.; Smithgall, T.E. Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. J. Biol. Chem., 2006, 281, 30907-30916.
48. Chen, S.; O'Reilly, L.P.; Smithgall, T.E.; Engen, J.R. Tyrosine phosphorylation in the SH3 domain disrupts negative regulatory interactions within the c-Abl kinase core. J. Mol. Biol., 2008, 383, 414-423.
49. Lionberger, J.M.; Wilson, M.B.; Smithgall, T.E. Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck. J. Biol. Chem., 2000, 275, 18581-18585.
50. Ye, D.; Wolff, N.; Li, L.; Zhang, S.; Ilaria, R.L. Jr. STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood, 2006, 107, 4917-4925.
51. Klejman, A.; Schreiner, S.J.; Nieborowska-Skorska, M.; Slupianek, A.; Wilson, M.; Smithgall, T.E.; Skorski, T. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J., 2002, 21, 5766-5774.
52. Poincloux, R.; Cougoule, C.; Daubon, T.; Maridonneau-Parini, I.; Le Cabec, V. Tyrosine-phosphorylated STAT5 accumulates on podosomes in Hck-transformed fibroblasts and chronic myeloid leukemia cells. J. Cell. Physiol., 2007, 213, 212-220.
53. Chatain, N.; Ziegler, P.; Fahrenkamp, D.; Jost, E.; Moriggl, R.; Schmitz-Van de Leur, H.; Müller-Newen, G. Src family kinases mediate cytoplasmic retention of activated STAT5 in BCR-ABLpositive cells. Oncogene, 2013, 32, 3587-3597.
54. Yamada, O.; Ozaki, K.; Furukawa, T.; Machida, M.; Wang, Y.H.; Motoji, T.; Mitsuishi, T.; Akiyama, M.; Yamada, H.; Kawauchi, K.; Matsuoka, R. Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1. Cell. Signal., 2011, 23, 1119-1127.
55. Lakshmikuttyamma, A.; Pastural, E.; Takahashi, N.; Sawada, K.; Sheridan, D.P.; DeCoteau, J.F.; Geyer, C.R. Bcr-Abl induces autocrine IGF-1 signaling. Oncogene, 2008, 27, 3831-3844.
56. Baruzzi, A.; Iacobucci, I.; Soverini, S.; Lowell, C.A.; Martinelli, G.; Berton, G. c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration. FEBS Lett., 2010, 584, 15-21.
57. Pene-Dumitrescu, T.; Peterson, L.F.; Donato, N.J.; Smithgall, T.E. An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259. Oncogene, 2008, 27, 7055-7069.
58. Azam, M.; Latek, R.R.; Daley, G.Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCRABL. Cell, 2008, 112, 831-843.
59. Juan, W.C.; Ong, S.T. The role of protein phosphorylation in therapy resistance and disease progression in chronic myelogenous leukemia. Prog. Mol. Biol. Trans. Sci., 2012, 106, 107-142.
60. Donato, N.J.; Wu, J.Y.; Stapley, J.; Gallick, G.; Lin, H.; Arlinghaus, R.; Talpaz, M. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood, 2003, 101, 690-698.
61. Hu, Y.; Swerdlow, S.; Duffy, T.M.; Weinmann, R.; Lee, F.Y.; Li, S. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc. Natl. Acad. Sci. USA, 2006, 103, 16870-16875.
62. Jalkanen, S.E.; Lahesmaa-Korpinen, A.M.; Heckman, C.A.; Rantanen, V.; Porkka, K.; Hautaniemi, S.; Mustjoki, S. Phosphoprotein profiling predicts response to tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients. Exp. Hematol., 2012, 40, 705-714.
63. Rubbi, L.; Titz, B.; Brown, L.; Galvan, E.; Komisopoulou, E.; Chen, S.S.; Low, T.; Tahmasian, M.; Skaggs, B.; Müschen, M.; Pellegrini, M.; Graeber, T.G. Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling. Sci. Signal., 2011, 4(166): ra18.
64. Hayette, S.; Chabane, K.; Michallet, M.; Michallat, E.; Cony-Makhoul, P.; Salesse, S.; Maguer-Satta, V.; Magaud, J.P.; Nicolini, F.E. Longitudinal studies of SRC family kinases in imatinib-and dasatinib-resistant chronic myelogenous leukemia patients. Leuk. Res., 2011, 35, 38-43.
65. Hu, Y.; Liu, Y.; Pelletier, S.; Buchdunger, E.; Warmuth, M.; Fabbro, D.; Hallek, M.; Van Etten, R.A.; Li, S. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced Blymphoblastic leukemia but not chronic myeloid leukemia. Nat. Genet., 2004, 36, 453-461.
66. Schenone, S.; Brullo, C.; Botta, M. Small molecules ATPcompetitive inhibitors of FLT3: A chemical overview. Curr. Med. Chem., 2008, 15, 3113-3132.
67. Mitina, O.; Warmuth, M.; Krause, G.; Hallek, M.; Obermeier, A. Src family tyrosine kinases phosphorylate Flt3 on juxtamembrane tyrosines and interfere with receptor maturation in a kinasedependent manner. Ann. Hematol., 2007, 86, 777-785.
68. Dos Santos, C.; Demur, C.; Bardet, V.; Prade-Houdellier, N.; Payrastre, B.; Récher, C. A critical role for Lyn in acute myeloid leukemia. Blood, 2008, 111, 2269-2279.
69. Saito, Y.; Kitamura, H.; Hijikata, A.; Tomizawa-Murasawa, M.; Tanaka, S.; Takagi, S.; Uchida, N.; Suzuki, N.; Sone, A.; Najima, Y.; Ozawa, H.; Wake, A.; Taniguchi, S.; Shultz, L.D.; Ohara, O.; Ishikawa, F. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci. Trans. Med., 2010, 2:17ra9.
70. MacKinnon, R.N.; Selan, C.; Wall, M.; Baker, E.; Nandurkar, H.; Campbell, L.J. The paradox of 20q11.21 amplification in a subset of cases of myeloid malignancy with chromosome 20 deletion. Genes Chromosomes Cancer, 2010, 49, 998-1013.
71. Pecquet, C.; Nyga, R.; Penard-Lacronique, V.; Smithgall, T.E.; Murakami, H.; Régnier, A.; Lassoued, K.; Gouilleux, F. The Src tyrosine kinase Hck is required for Tel-Abl-but not for Tel-Jak2-induced cell transformation. Oncogene, 2007, 26, 1577-1585.
72. Yang, C.; Lu, P.; Lee, F.Y.; Chadburn, A.; Barrientos, J.C.; Leonard, J.P.; Ye, F.; Zhang, D.; Knowles, D.M.; Wang, Y.L. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib. Leukemia, 2008, 22, 1755-1766.
73. Hallek, M.; Neumann, C.; Schäffer, M.; Danhauser-Riedl, S.; von Bubnoff, N.; de Vos, G.; Druker, B.J.; Yasukawa, K.; Griffin, J.D.; Emmerich, B. Signal transduction of interleukin-6 involves tyrosine phosphorylation of multiple cytosolic proteins and activation of Src-family kinases Fyn, Hck, and Lyn in multiple myeloma cell lines. Exp. Hematol., 1997, 25, 1367-1377.
74. Hausherr, A.; Tavares, R.; Schäffer, M.; Obermeier, A.; Miksch, C.; Mitina, O.; Ellwart, J.; Hallek, M.; Krause, G. Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases. Oncogene, 2007, 26, 4987-4998.
75. Podar, K.; Mostoslavsky, G.; Sattler, M.; Tai, Y.T.; Hayashi, T.; Catley, L.P.; Hideshima, T.; Mulligan, R.C.; Chauhan, D.; Anderson, K.C. Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells. J. Biol. Chem., 2004, 279, 21658-21665.
76. Poincloux, R.; Al Saati, T.; Maridonneau-Parini, I.; Le Cabec, V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane-and lysosomeassociated isoforms. Eur. J. Cancer, 2009, 45, 321-327.
77. Lamers, S.L.; Fogel, G.B.; Singer, E.J.; Salemi, M.; Nolan, D.J.; Huysentruyt, L.C.; McGrath, M.S. HIV-1 Nef in macrophagemediated disease pathogenesis. Int. Rev. Immunol., 2012, 31, 432-450.
78. Ahmad, N.; Venkatesan, S. Nef protein of HIV-1 is a transcriptional repressor of HIV-1 LTR. Science, 1988, 241, 1481-1485.
79. Trible, R.P.; Emert-Sedlak, L.; Smithgall, T.E. HIV-1 Nef selectively activates Src family kinases Hck, Lyn, and c-Src through direct SH3 domain interaction. J. Biol. Chem., 2006, 281, 27029-27038.
80. Abraham, L.; Fackler, O.T. HIV-1 Nef: A multifaceted modulator of T cell receptor signaling. Cell. Commun. Signal., 2012, 10, 39.
81. Nazari-Shafti, T.Z.; Freisinger, E.; Roy, U.; Bulot, C.T.; Senst, C.; Dupin, C.L.; Chaffin, A.E.; Srivastava, S.K.; Mondal, D.; Alt, E.U.; Izadpanah, R. Mesenchymal stem cell derived hematopoietic cells are permissive to HIV-1 infection. Retrovirology, 2011, 8, 3.
82. Grzesiek, S.; Bax, A.; Hu, J.S.; Kaufman, J.; Palmer, I.; Stahl, S.J.; Tjandra, N.; Wingfield, P.T. Refined solution structure and backbone dynamics of HIV-1 Nef. Protein Sci., 1997, 6, 1248-1263.
83. Arold, S.; Franken, P.; Strub, M.P.; Hoh, F.; Benichou, S.; Benarous, R.; Dumas, C. The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling. Structure, 1997, 5, 1361-1372.
84. Alvarado, J. J.; Tarafdar, S.; Yeh, J. I.; Smithgall, T. E. Interaction with the Src homology (SH3-SH2) region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment. J. Biol. Chem. 2014, 289, 28539-28553.
85. Saksela, K.; Cheng, G.; Baltimore, D. Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for downregulation of CD4. EMBO J., 1995, 14, 484-491.
86. Porter, M.; Schindler, T.; Kuriyan, J.; Miller, W.T. Reciprocal regulation of Hck activity by phosphorylation of Tyr(527) and Tyr(416). Effect of introducing a high affinity intramolecular SH2 ligand. J. Biol. Chem., 2000, 275, 2721-2726.
87. Choi, H. J.; Smithgall, T.E. Conserved residues in the HIV-1 Nef hydrophobic pocket are essential for recruitment and activation of the Hck tyrosine kinase. J. Mol. Biol., 2004, 343, 1255-1268.
88. Lee, C.H.; Leung, B.; Lemmon, M.A.; Zheng, J.; Cowburn, D.; Kuriyan, J.; Saksela, K. A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein. EMBO J., 1995, 14, 5006-5015.
89. Briggs, S.D.; Sharkey, M.; Stevenson, M.; Smithgall, T.E. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J. Biol. Chem., 1997, 272, 17899-17902.
90. Lee, C.H.; Saksela, K.; Mirza, U.A.; Chait, B.T.; Kuriyan, J. Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain. Cell, 1996, 85, 931-942.
91. Mwimanzi, P.; Hasan, Z.; Hassan, R.; Suzu, S.; Takiguchi, M.; Ueno, T. Effects of naturally-arising HIV Nef mutations on cytotoxic T lymphocyte recognition and Nef's functionality in primary macrophages. Retrovirology, 2011, 8, 50.
92. Moarefi, I.; LaFevre-Bernt, M.; Sicheri, F.; Huse, M.; Lee, C.H.; Kuriyan, J.; Miller, W.T. Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature, 1997, 385, 650-653.
93. Tokunaga, K.; Kiyokawa, E.; Nakaya, M.; Otsuka, N.; Kojima, A.; Kurata, T.; Matsuda, M. Inhibition of human immunodeficiency virus type 1 virion entry by dominant-negative Hck. J. Virol., 1998, 72, 6257-6259.
94. Suzu, S.; Harada, H.; Matsumoto, T.; Okada, S. HIV-1 Nef interferes with M-CSF receptor signaling through Hck activation and inhibits M-CSF bioactivities. Blood, 2005, 105, 3230-3237.
95. Ye, H.; Choi, H.J.; Poe, J.; Smithgall, T.E. Oligomerization is required for HIV-1 Nef-induced activation of the Src family protein-tyrosine kinase, Hck. Biochemistry, 2004, 43, 15775-15784.
96. Komuro, I.; Yokota, Y.; Yasuda, S.; Iwamoto, A.; Kagawa, K.S. CSF-induced and HIV-1-mediated distinct regulation of Hck and C/EBPbeta represent a heterogeneous susceptibility of monocytederived macrophages to M-tropic HIV-1 infection. J. Exp. Med., 2003, 198, 443-453.
97. Hanna, Z.; Weng, X.; Kay, D.G.; Poudrier, J.; Lowell, C.; Jolicoeur, P. The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck. J. Virol., 2001, 75, 9378-9392.
98. Trible, R.P.; Emert-Sedlak, L.; Wales, T.E.; Ayyavoo, V.; Engen, J.R.; Smithgall, T.E. Allosteric loss-of-function mutations in HIV-1 Nef from a long-term non-progressor. J. Mol. Biol., 2007, 374, 121-129.
99. Meuwissen, P.J.; Stolp, B.; Iannucci, V.; Vermeire, J.; Naessens, E.; Saksela, K.; Geyer, M.; Vanham, G.; Arien, K.K.; Fackler, O.T.; Verhasselt, B. Identification of a highly conserved valineglycine-phenylalanine amino acid triplet required for HIV-1 Nef function. Retrovirology, 2012, 9, 34.
100. Hassan, R.; Suzu, S.; Hiyoshi, M.; Takahashi-Makise, N.; Ueno, T.; Agatsuma, T.; Akari, H.; Komano, J.; Takebe, Y.; Motoyoshi, K.; Okada, S. Dys-regulated activation of a Src tyroine kinase Hck at the Golgi disturbs N-glycosylation of a cytokine receptor Fms. J. Cell. Physiol., 2009, 221, 458-468.
101. Hiyoshi, M.; Takahashi-Makise, N.; Yoshidomi, Y.; Chutiwitoonchai, N.; Chihara, T.; Okada, M.; Nakamura, N.; Okada, S.; Suzu, S. HIV-1 Nef perturbs the function, structure, and signaling of the Golgi through the Src kinase Hck. J. Cell. Physiol., 2012, 227, 1090-1097.
102. Kim, M.O.; Suh, H.S.; Si, Q.; Terman, B.I.; Lee, S.C. Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia: role of Hck tyrosine kinase and implications for AIDS dementia. J. Virol., 2006, 80, 62-72.
103. Olivieri, K.C.; Agopian, K.A.; Mukerji, J.; Gabuzda, D. Evidence for adaptive evolution at the divergence between lymphoid and brain HIV-1 nef genes. AIDS Res. Hum. Retroviruses, 2010, 26, 495-500.
104. Suh, H.S.; Kim, M.O.; Lee, S.C. Inhibition of granulocytemacrophage colony-stimulating factor signaling and microglial proliferation by anti-CD45RO: Role of Hck tyrosine kinase and phosphatidylinositol 3-kinase/Akt. J. Immunol., 2005, 174, 2712-2719.
105. Biggs, T.E.; Cooke, S.J.; Barton, C.H.; Harris, M.P.; Saksela, K.; Mann, D.A. Induction of activator protein 1 (AP-1) in macrophages by human immunodeficiency virus type-1 NEF is a cell-typespecific response that requires both hck and MAPK signaling events. J. Mol. Biol., 1999, 290, 21-35.
106. Vérollet, C.; Zhang, Y.M.; Le Cabec, V.; Mazzolini, J.; Charrière, G.; Labrousse, A.; Bouchet, J.; Medina, I.; Biessen, E.; Niedergang, F.; Bénichou, S.; Maridonneau-Parini, I. HIV-1 Nef triggers macrophage fusion in a p61Hck-and protease-dependent manner. J. Immunol., 2010, 184, 7030-7039.
107. Järviluoma, A.; Strandin, T.; Lülf, S.; Bouchet, J.; Mäkelä, A.R.; Geyer, M.; Benichou, S.; Saksela, K. High-affinity target binding engineered via fusion of a single-domain antibody fragment with a ligand-tailored SH3 domain. PLoS One, 2012, 7: e40331.
108. Bouchet, J.; Hérate, C.; Guenzel, C.A.; Vérollet, C.; Järviluoma, A.; Mazzolini, J.; Rafie, S.; Chames, P.; Baty, D.; Saksela, K.; Niedergang, F.; Maridonneau-Parini, I.; Benichou, S. Singledomain antibody-SH3 fusions for efficient neutralization of HIV-1 Nef functions. J. Virol., 2012, 86, 4856-4867.
109. Komuro, I.; Sunazuka, T.; Akagawa, K.S.; Yokota, Y.; Iwamoto, A.; Omura, S. Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPbeta. Proc. Natl. Acad. Sci. USA, 2008, 105, 12509-12514.
110. Shi, X.; Opi, S.; Lugari, A.; Restouin, A.; Coursindel, T.; Parrot, I.; Perez, J.; Madore, E.; Zimmermann, P.; Corbeil, J.; Huang, M.; Arold, S.T.; Collette, Y.; Morelli, X. Identification and biophysical assessment of the molecular recognition mechanisms between the human haemopoietic cell kinase Src homology domain 3 and ALG-2-interacting protein X. Biochem. J., 2010, 431, 93-102.
111. Odorizzi, G. The multiple personalities of Alix. J. Cell Sci., 2006, 119, 3025-3032.
112. Dowlatshahi, D.P.; Sandrin, V.; Vivona, S.; Shaler, T.A.; Kaiser, S.E.; Melandri, F.; Sundquist, W.I.; Kopito, R.R. ALIX is a Lys63-specific polyubiquitin binding protein that functions in retrovirus budding. Dev. Cell., 2012, 23, 1247-1254.
113. Shi, X.; Betzi, S.; Lugari, A.; Opi, S.; Restouin, A.; Parrot, I.; Martinez, J.; Zimmermann, P.; Lecine, P.; Huang, M.; Arold, S.T.; Collette, Y.; Morelli, X. Structural recognition mechanisms between human Src homology domain 3 (SH3) and ALG-2-interacting protein X (Alix). FEBS Lett., 2012, 586, 1759-1764.
114. Lambert, A.A.; Barabé, F.; Gilbert, C.; Tremblay, M.J. DCIRmediated enhancement of HIV-1 infection requires the ITIMassociated signal transduction pathway. Blood, 2011, 117, 6589-6599.
115. Malim, M.H.; Emerman, M. HIV-1 accessory proteins ensuring viral survival in a hostile environment. Cell Host Microbe, 2008, 3, 388-398.
116. Gallerano, D.; Devanaboyina, S.C.; Swoboda, I.; Linhart, B.; Mittermann, I.; Keller, W.; Valenta, R. Biophysical characterization of recombinant HIV-1 subtype C virus infectivity factor. Amino Acids, 2011, 40, 981-989.
117. Marcsisin, S.R.; Narute, P.S.; Emert-Sedlak, L.A.; Kloczewiak, M.; Smithgall, T.E.; Engen, J.R. On the solution conformation and dynamics of the HIV-1 viral infectivity factor. J. Mol. Biol., 2011, 410, 1008-1022.
118. Hanke, J.H.; Gardner, J.P.; Dow, R.L.; Changelian, P.S.; Brissette, W.H.; Weringer, E.J.; Pollok, B.A.; Connelly, P.A. 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, 695-701.
119. Liu, Y.; Bishop, A.; Witucki, L.; Kraybill, B.; Shimizu, E.; Tsien, J.; Ubersax, J.; Blethrow, J.; Morgan, D.O.; Shokat, K.M. Structural basis for selective inhibition of Src family kinases by PP1. Chem. Biol., 1999, 6, 671-678.
120. Schindler, T.; Sicheri, F.; Pico, A.; Gazit, A.; Levitzki, A.; Kuriyan, J. Crystal structure of Hck in complex with a Src familyselective tyrosine kinase inhibitor. Mol. Cell., 1999, 3, 639-648.
121. Burchat, A.; Borhani, D.W.; Calderwood, D.J.; Hirst, G.C.; Li, B.; Stachlewits, R.F. Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection. Bioorg. Med. Chem. Lett., 2006, 16, 118-122.
122. Bishop, A.C.; Ubersax, J.A.; Petsch, D.T.; Matheos, D.P.; Gray, N.S.; Blethrow, J.; Shimizu, E.; Tsien, J.Z.; Schultz, P.G.; Rose, M.D.; Wood, J.L.; Morgan, D.O.; Shokat, K.M. A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature, 2000, 407, 395-401.
123. Pene-Dumitrescu, T.; Shu, S.T.; Wales, T.E.; Alvarado, J.J.; Shi, H.; Narute, P.; Moroco, J.A.; Yeh, J.I.; Engen, J.R.; Smithgall, T.E. HIV-1 Nef interaction influences the ATP-binding site of the Srcfamily kinase, Hck. BMC Chem. Biol., 2012, 12, 1.
124. Krishnamurty, R.; Brigham, J.L.; Leonard, S.E.; Ranjitkar, P.; Larson, E.T.; Dale, E.J.; Merritt, E.A.; Maly, D.J. Active site profiling reveals coupling between domains in SRC-family kinases. Nat. Chem. Biol., 2013, 9, 43-50.
125. Rauch, J.; Volinsky, N.; Romano, D.; Kolch, W. The secret life of kinases: functions beyond catalysis. Cell Commun. Signal., 2011, 9, 23.
126. Tintori, C.; Laurenzana, I.; La Rocca, F.; Falchi, F.; Carraro, F.; Ruiz, A.; Esté, J.A.; Kissova, M.; Crespan, E.; Maga, G.; Biava, M.; Brullo, C.; Schenone, S.; Botta, M. Identification of Hck inhibitors as hits for the development of antileukemia and anti-HIV agents. ChemMedChem., 2013, 8, 1353-1360.
127. Radi, M.; Tintori, C.; Musumeci, F.; Brullo, C.; Zamperini, C.; Dreassi, E.; Fallacara, A.L.; Vignaroli, G.; Crespan, E.; Zanoli, S.; Laurenzana, I.; Filippi, I.; Maga, G.; Schenone, S.; Angelucci, A.; Botta. M. Design, synthesis, and biological evaluation of pyrazolo[ 3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant. J. Med. Chem., 2013, 56, 5382-5394.
128. Schenone, S.; Radi, M.; Musumeci, F.; Brullo, C.; Botta, M. Biologically driven synthesis of pyrazolo [3,4-d]pyrimidines as protein kinase inhibitors: an old scaffold as a new tool for medicinal chemistry and chemical biology studies. Chem. Rev., 2014, 114(14), 7189-7283.
129. Saito, Y.; Yuki, H.; Kuratani, M.; Hashizume, Y.; Takagi, S.; Honma, T.; Tanaka, A.; Shirouzu, M.; Mikuni, J.; Handa, N.; Ogahara, I.; Sone, A.; Najima, Y.; Tomabechi, Y.; Wakiyama, M.; Uchida, N.; Tomizawa-Murasawa, M.; Kaneko, A.; Tanaka, S.; Suzuki, N.; Kajita, H.; Aoki, Y.; Ohara, O.; Shultz, L.D.; Fukami, T.; Goto, T.; Taniguchi, S.; Yokoyama, S.; Ishikawa, F. A pyrrolopyrimidine derivative targets human primary AML stem cells in vivo. Sci. Trans. Med., 2013, 5, 181ra5.
130. Parker, L.J.; Taruya, S.; Tsuganezawa, K.; Ogawa, N.; Mikuni, J.; Honda, K.; Tomabechi, Y.; Handa, N.; Shirouzu, M.; Yokoyama, S.; Tanaka, A. Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002. Acta Crystallogr. D Biol. Crystallogr., 2014, 70, 392-404.
131. Calderwood, D.J.; Johnston, D.N.; Munschauer, R.; Rafferty, P. Pyrrolo [2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck. Bioorg. Med. Chem. Lett., 2002, 12, 1683-1686.
132. Wilson, M.B.; Schreiner, S.J.; Choi, H.J.; Kamens, J.; Smithgall, T.E. Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis. Oncogene, 2002, 21, 8075-8088.
133. Green, T.P.; Fennell, M.; Whittaker, R.; Curwen, J.; Jacobs, V.; Allen, J.; Logie, A.; Hargreaves, J.; Hickinson, D.M.; Wilkinson, R.W.; Elvin, P.; Boyer, B.; Carragher, N.; Plé, P.A.; Bermingham, A.; Holdgate, G.A.; Ward, W.H.; Hennequin, L.F.; Davies, B.R.; Costello, G.F. Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol. Oncol., 2009, 3, 248-261.
134. Gwanmesia, P.M.; Romanski, A.; Schwarz, K.; Bacic, B.; Ruthardt, M.; Ottmann, O.G. The effect of the dual Src/Abl kinase inhibitor AZD0530 on Philadelphia positive leukaemia cell lines. BMC Cancer, 2009, 9, 53.
135. Musumeci, F.; Schenone, S.; Brullo, C.; Botta, M. An update on dual Src/Abl inhibitors. Future Med. Chem., 2012, 4, 799-822.
136. Summy, J.M.; Trevino, J.G.; Lesslie, D.P.; Baker, C.H.; Shakespeare, W.C.; Wang, Y.; Sundaramoorthi, R.; Metcalf, C.A 3rd; Keats, J.A.; Sawyer, T.K.; Gallick, G.E. AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes. Mol. Cancer Ther., 2005, 4, 1900-1911.
137. Moy, F.J.; Lee, A.; Gavrin, L.K.; Xu, Z.B.; Sievers, A.; Kieras, E.; Stochaj, W.; Mosyak, L.; McKew, J.; Tsao, D.H. Novel synthesis and structural characterization of a high-affinity paramagnetic kinase probe for the identification of non-ATP site binders by nuclear magnetic resonance. J. Med. Chem., 2010, 53, 1238-1249.
138. Sabat, M.; Vanrens, J.C.; Brugel, T.A.; Maier, J.; Laufersweiler, M.J.; Golebiowski, A.; De, B.; Easwaran, V.; Hsieh, L.C.; Rosegen, J.; Berberich, S.; Suchanek, E.; Janusz, M.J. The development of novel 1,2-dihydro-pyrimido [4,5-c]pyridazine based inhibitors of lymphocyte specific kinase (Lck). Bioorg. Med. Chem. Lett., 2006, 16, 4257-4261
139. Wityak, J.; Das, J.; Moquin, R.V.; Shen, Z.; Lin, J.; Chen, P.; Doweyko, A.M.; Pitt, S.; Pang, S.; Shen, D.R.; Fang, Q.; de Fex, H.F.; Schieven, G.L.; Kanner, S.B.; Barrish, J.C. Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56(Lck). Bioorg. Med. Chem. Lett., 2003, 13, 4007-4010.
140. Chen, P.; Norris, D.; Das, J.; Spergel, S.H.; Wityak, J.; Leith, L.; Zhao, R.; Chen, B.C.; Pitt, S.; Pang, S.; Shen, D.R.; Zhang, R.; De Fex, H.F.; Doweyko, A.M.; McIntyre, K.W.; Shuster, D.J.; Behnia, K.; Schieven, G.L.; Barrish, J.C. Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 6061-6066.
141. Lombardo, L.J.; Lee, F.Y.; Chen, P.; Norris, D.; Barrish, J.C.; Behnia, K.; Castaneda, S.; Cornelius, L.A.; Das, J.; Doweyko, A.M.; Fairchild, C.; Hunt, J.T.; Inigo, I.; Johnston, K.; Kamath, A.; Kan, D.; Klei, H.; Marathe, P.; Pang, S.; Peterson, R.; Pitt, S.; Schieven, G.L.; Schmidt, R.J.; Tokarski, J.; Wen, M.L.; Wityak, J.; Borzilleri, R.M. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem., 2004, 47, 6658-6661.
142. Shah, N.P.; Tran, C.; Lee, F.Y.; Chen, P.; Norris, D.; Sawyers, C.L. Overriding imatinib resistance with a novel Abl inhibitors. Science, 2004, 305, 399-401.
143. O'Hare, T.; Walters, D.K.; Stoffregen, E.P.; Jia, T.; Manley, P.W.; Mestan, J.; Cowan-Jacob, S.W.; Lee, F.Y.; Heinrich, M.C.; Deininger, M.W.; Druker, B.J. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res., 2005, 65, 4500-4505.
144. Hantschel, O.; Rix, U.; Schmidt, U.; Bürckstümmer, T.; Kneidinger, M.; Schütze, G.; Colinge, J.; Bennett, K.L.; Ellmeier, W.; Valent, P.; Superti-Furga, G. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc. Natl. Acad. Sci. USA, 2007, 104, 13283-13288.
145. Lindauer, M.; Hochhaus, A. Dasatinib. Recent results. Cancer Res., 2014, 201, 27-65.
146. Nam, S.; Williams, A.; Vultur, A.; List, A.; Bhalla, K.; Smith, D.; Lee, F.Y.; Jove, R. Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol. Cancer Ther., 2007, 6, 1400-1405.
147. Patricelli, M.P.; Szardenings, A.K.; Liyanage, M.; Nomanbhoy, T.K.; Wu, M.; Weissig, H.; Aban, A.; Chun, D.; Tanner, S.; Kozarich, J.W. Functional interrogation of the kinome using nucleotide acyl phosphates. Biochemistry, 2007, 46, 350-358.
148. Patricelli, M.P.; Nomanbhoy, T.K.; Wu, J.; Brown, H.; Zhou, D.; Zhang, J.; Jagannathan, S.; Aban, A.; Okerberg. E.; Herring, C.; Nordin, B.; Weissig, H.; Yang, Q.; Lee, J.D.; Gray, N.S.; Kozarich, J.W. In situ kinase profiling reveals functionally relevant properties of native kinases. Chem. Biol., 2011, 18, 699-710.
149. Sabat, M.; VanRens, J.C.; Laufersweiler, M.J.; Brugel, T.A.; Maier, J.; Golebiowski, A.; De, B.; Easwaran, V.; Hsieh, L.C.; Walter, R.L.; Mekel, M.J.; Evdokimov, A.; Janusz, M. J. The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck). Bioorg. Med. Chem. Lett. 2006, 16, 5973-5977.
150. Gallagher, T.F.; Seibel, G.L.; Kassis, S.; Laydon, J.T.; Blumenthal, M.J.; Lee, J.C.; Lee, D.; Boehm, J.C.; Fier-Thompson, S.M.; Abt, J.W.; Soreson, M.E.; Smietana, J.M.; Hall, R.F.; Garigipati, R.S.; Bender, P.E.; Erhard, K.F.; Krog, A.J.; Hofmann, G.A.; Sheldrake, P.L.; McDonnell, P.C.; Kumar, S.; Young, P.R.; Adams, J.L. Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg. Med. Chem., 1997, 5, 49-64.
151. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P.F.; Gilmore, T.; Graham, A.G.; Grob, P.M.; Hickey, E.R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol., 2002, 9, 268-272.
152. Chen, P.; Doweyko, A.M.; Norris, D.; Gu, H.H.; Spergel, S.H.; Das, J.; Moquin, R.V.; Lin, J.; Wityak, J.; Iwanowicz, E.J.; McIntyre, K.W.; Shuster, D.J.; Behnia, K.; Chong, S.; de Fex, H.; Pang, S.; Pitt, S.; Shen, D.R.; Thrall, S.; Stanley, P.; Kocy, O.R.; Witmer, M.R.; Kanner, S.B.; Schieven, G.L.; Barrish, J.C. Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo-[1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity. J. Med. Chem., 2004, 47, 4517-4529.
153. Boschelli, D.H. ; Ye, F. ; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J. Med. Chem., 2001, 44, 3965-3977.
154. Golas, J.M.; Arndt, K.; Etienne, C.; Lucas, J.; Nardin, D.; Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D.H.; Boschelli, F. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res., 2003, 63, 375-381.
155. Liu, X.F.; Xiang, L.; FitzGerald, D.J.; Pastan, I. Antitumor effects of immunotoxins are enhanced by lowering HCK or treatment with SRC kinase inhibitors. Mol. Cancer Ther. 2014, 13, 82-89.
156. Sun, X.; Phan, T.N.; Jung, S.H.; Kim, S.Y.; Cho, J.U.; Lee, H.; Woo, S.H.; Park, T.K.; Yang, B.S. LCB 03-0110, a novel pandiscoidin domain receptor/c-Src family tyrosine kinase inhibitor, suppresses scar formation by inhibiting fibroblast and macrophage activation. J. Pharmacol. Exp. Ther., 2012, 340, 510-519.
157. Jung, S.H.; Sun, X.; Ryu, W.S.; Yang, B.S. Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03-0110, prevents allergic contact dermatitis in mice. Br. J. Dermatol., 2013, 168, 112-119.
158. Zhang, G.; Ren, P.; Gray, N.S.; Sim, T.; Wang, X.; Liu, Y.; Che, J.; Dong, W.; Tian, S.S.; Sandberg, M.L.; Spalding, T.A.; Romeo, R.; Iskandar, M.; Wang, Z.; Seidel, H.M.; Karanewsky, D.S.; He, Y. Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. Part II. Bioorg. Med. Chem. Lett., 2009, 19, 6691-6695.
159. Seeliger, M.A.; Ranjitkar, P.; Kasap, C.; Shan, Y.; Shaw, D.E.; Shah, N.P.; Kuriyan, J.; Maly, D.J. Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations. Cancer Res., 2009, 69, 2384-2392.
160. Ranjitkar, P.; Brock, A.M.; Maly, D.J. Affinity reagents that target a specific inactive form of protein kinases. Chem. Biol., 2010, 17, 195-206.
161. Ranjitkar, P.; Perera, B.G.; Swaney, D.L.; Hari, S.B.; Larson, E.T.; Krishnamurty, R.; Merritt, E.A.; Villén, J.; Maly, D.J. Affinitybased probes based on type II kinase inhibitors. J. Am. Chem. Soc., 2012, 134, 19017-19025.
162. Hari, S.B.; Perera, B.G.; Ranjitkar, P.; Seeliger, M.A.; Maly, D.J. Conformation-selective inhibitors reveal differences in the activation and phosphate-binding loops of the tyrosine kinases Abl and Src. ACS Chem. Biol., 2013, 8, 2734-2743.
163. Fang, Z.; Grütter, C.; Rauh, D. Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem. Biol., 2013, 8, 58-70.
164. Hill, Z.B.; Perera, G.K.; Maly, D.J. A Chemical genetic method for generating bivalent inhibitors of protein kinases. J. Am. Chem. Soc., 2009, 131, 6686-6688.
165. Keppler, A.; Kindermann, M.; Gendreizig, S.; Pick, H.; Vogel, H.; Johnsson, K. Labeling of fusion proteins of O6-alkylguanine-DNA alkyltransferase with small molecules in vivo and in vitro. Methods, 2004, 32, 437-444.
166. Hill, Z.B.; Perera, G.K.; Maly, D.J. Bivalent inhibitors of the tyrosine kinases ABL and SRC: determinants of potency and selectivity. Mol. Biosyst., 2011, 7, 447-456.
167. Emert-Sedlak, L.; Kodama, T.; Lerner, E.C.; Dai, W.; Foster, C.; Day, B.W.; Lazo, J.S.; Smithgall, T.E. Chemical library screens targeting an HIV-1 accessory factor/host cell kinase complex identify novel antiretroviral compounds. ACS Chem. Biol., 2009, 4, 939-947.
168. Oneyama, C.; Agatsuma, T.; Kanda, Y.; Nakano, H.; Sharma, S.V.; Nakano, S.; Narazaki, F.; Tatsuta, K. Synthetic inhibitors of proline-rich ligand-mediated protein-protein interaction: potent analogs of UCS15A. Chem. Biol., 2003, 10, 443-451.
169. Chutiwitoonchai, N.; Hiyoshi, M.; Mwimanzi, P.; Ueno, T.; Adachi, A.; Ode, H.; Sato, H.; Fackler, O.T.; Okada, S.; Suzu, S. The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement. PLoS One, 2011, 6, e27696.
170. Smithgall, T.E.; Thomas, G. Small molecule inhibitors of the HIV-1 virulence factor, Nef. Drug Discov. Today Technol., 2013, 10, e523-9.
171. Trible, R.P.; Narute, P.; Emert-Sedlak, L.A.; Alvarado, J.J.; Atkins, K.; Thomas, L.; Kodama, T.; Yanamala, N.; Korotchenko, V.; Day, B.W.; Thomas, G.; Smithgall, T.E. Discovery of a diaminoquinoxaline benzenesulfonamide antagonist of HIV-1 Nef function using a yeast-based phenotypic screen. Retrovirology, 2013, 10, 135.
172. Ballana, E.; Pauls, E.; Clotet, B.; Perron-Sierra, F.; Tucker, G.C.; Esté, J.A. β5 integrin is the major contributor to the αVintegrinmediated blockade of HIV-1 replication. J. Immunol., 2011, 186, 464-470.
173. Smithgall, T.E.; Emert-Sedlak, L.A.; Day, B.W.; Zhao, J.; Iyer, P.C. Compounds for treating hiv and methods for using the compounds. WO Patent WO2014 074628, May 15, 2014.