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Chemical Compound Review

CHEMBL358725     5-[[5-[[(2S)-1-carboxy-3-oxo- propan-2...

Synonyms: AC1NS226
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Disease relevance of Inhibitor 4

  • Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration [1].
  • We also examined deletion of cyclin-dependent kinase inhibitor 4 (INK4) genes and mutation of p53 gene in combination with changes in the HTLV-I genome in acute type ATL to test whether host genetic changes promoted the malignant transformation of ATL cells that carry putative CTL escape mutations [2].
  • We have developed efficient syntheses of the HIV-1 protease inhibitor 4 and its analogues, which incorporate the pyrrolidone scaffold 2 as P1-P2 moiety [3].
  • Inhibition of p56lck activity by the specific inhibitor 4-amino-6-hydroxyflavone revealed a decrease of proliferation of the T-cell line Jurkat, but not of the Burkitt's lymphoma cell lines [4].
  • Four key factors have been revealed as involved in the generation of sodium-dependent hypertension: 1) genetic or acquired defect in renal sodium excretion; 2) dietary sodium intake; 3) natriuretic hormone as sodium inhibitor; 4) sodium for calcium exchange in smooth muscle and plasma membranes [5].

Psychiatry related information on Inhibitor 4

  • On challenge, it was noted that locomotor activity was significantly higher in mice injected repeatedly with the stimulant alone and in those mice treated with the inhibitor 4 h after the stimulant injection compared to the saline-treated control mice [6].

High impact information on Inhibitor 4

  • To determine the consequence of aPKCiota/lambda tyrosine phosphorylation, the membrane binding assay was supplemented with the Src-specific tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine (PP2) [7].
  • Phosphorylation is blocked by the Src kinase family inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) [8].
  • Nevertheless, OAG-induced Ca2+ entry bore the hallmarks of TRPC6 function; it was inhibited by protein kinase C and blocked by the Src-kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) [9].
  • Genistein and the Src kinase family inhibitor, 4-amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, inhibited MBP-stimulated phosphorylation of Akt [10].
  • Induction of Cbl phosphorylation upon EphA activation appeared to be dependent upon Src family kinase activity, as Cbl phosphorylation was selectively abrogated by the Src family inhibitor 4-amino-5(4-chlorophenyl-7-(tert-butyl)pyrazolo[3,4-d]pyrimidine, while EphA phosphorylation was unimpaired [11].

Chemical compound and disease context of Inhibitor 4


Biological context of Inhibitor 4


Anatomical context of Inhibitor 4

  • Neutrophil preincubation with the Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine and the Syk tyrosine kinase inhibitor trans-3,3',4,5'-tetrahydrozystilbene significantly reduced the release of S100A8/A9, suggesting that the Src tyrosine kinase family and Syk were involved [20].
  • METHODS: Confluent monolayers of human umbilical vein endothelial cells were exposed to saline solution, TNF-alpha (100 U/mL) or TNF and the Src-tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine [21].

Associations of Inhibitor 4 with other chemical compounds


Gene context of Inhibitor 4

  • Here, we demonstrate that PARP-1-/- cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cells are sensitive to the PARP inhibitor 4-amino-1,8-napthalamide [27].
  • Of the 12 subjects who had a clinically significant > or = 15% change in the INR while receiving either COX-2 inhibitor, 4 showed this change for both agents [28].
  • Avena seedlings grown in the presence of the plant tetrapyrrole synthesis inhibitor 4-amino-5-hexynoic acid contain less than 10% of the spectrally detectable phytochrome levels found in untreated seedlings, but continue to accumulate phytochrome apoprotein (Elich, T. D., and Lagarias, J. C. (1988) Plant Physiol. 88, 747-751) [29].
  • We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM) [30].
  • Tyrosine phosphorylation of the delta-OR appeared to require the actions of a Src-like protein tyrosine kinase, since the Src inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)-pyrazolo-[3,4-d]-pyrimidine (PP1) attenuated this response [31].


  1. Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK. Seefeld, M.A., Miller, W.H., Newlander, K.A., Burgess, W.J., DeWolf, W.E., Elkins, P.A., Head, M.S., Jakas, D.R., Janson, C.A., Keller, P.M., Manley, P.J., Moore, T.D., Payne, D.J., Pearson, S., Polizzi, B.J., Qiu, X., Rittenhouse, S.F., Uzinskas, I.N., Wallis, N.G., Huffman, W.F. J. Med. Chem. (2003) [Pubmed]
  2. HTLV-I viral escape and host genetic changes in the development of adult T cell leukemia. Furukawa, Y., Tara, M., Izumo, S., Arimura, K., Osame, M. Int. J. Cancer (2006) [Pubmed]
  3. Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties. Kazmierski, W.M., Andrews, W., Furfine, E., Spaltenstein, A., Wright, L. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  4. Expression of p56lck in B-cell neoplasias. Von Knethen, A., Abts, H., Kube, D., Diehl, V., Tesch, H. Leuk. Lymphoma (1997) [Pubmed]
  5. Erythrocyte molecular shape modifications in the primary hypertension. Tripşa, M.F., Zaciu, A. Revue roumaine de physiologie (Bucharest, Romania : 1990) (1990) [Pubmed]
  6. Suppressive effect of cycloheximide on behavioral sensitization to methamphetamine in mice. Shimosato, K., Saito, T. Eur. J. Pharmacol. (1993) [Pubmed]
  7. Src-dependent aprotein kinase C iota/lambda (aPKCiota/lambda) tyrosine phosphorylation is required for aPKCiota/lambda association with Rab2 and glyceraldehyde-3-phosphate dehydrogenase on pre-golgi intermediates. Tisdale, E.J., Artalejo, C.R. J. Biol. Chem. (2006) [Pubmed]
  8. Src kinase activates endothelial nitric-oxide synthase by phosphorylating Tyr-83. Fulton, D., Church, J.E., Ruan, L., Li, C., Sood, S.G., Kemp, B.E., Jennings, I.G., Venema, R.C. J. Biol. Chem. (2005) [Pubmed]
  9. Role of endogenous TRPC6 channels in Ca2+ signal generation in A7r5 smooth muscle cells. Soboloff, J., Spassova, M., Xu, W., He, L.P., Cuesta, N., Gill, D.L. J. Biol. Chem. (2005) [Pubmed]
  10. Eosinophil major basic protein stimulates neutrophil superoxide production by a class IA phosphoinositide 3-kinase and protein kinase C-zeta-dependent pathway. Shenoy, N.G., Gleich, G.J., Thomas, L.L. J. Immunol. (2003) [Pubmed]
  11. Ephrin-A1 induces c-Cbl phosphorylation and EphA receptor down-regulation in T cells. Sharfe, N., Freywald, A., Toro, A., Roifman, C.M. J. Immunol. (2003) [Pubmed]
  12. Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold. Kazmierski, W.M., Furfine, E., Gray-Nunez, Y., Spaltenstein, A., Wright, L. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  13. Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. Katsura, H., Obata, K., Mizushima, T., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T., Sakagami, M., Noguchi, K. J. Neurosci. (2006) [Pubmed]
  14. Attempts to make sense of the antiphospholipid syndrome. Vermylen, J., Carreras, L.O., Arnout, J. J. Thromb. Haemost. (2007) [Pubmed]
  15. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors. Ghosh, A.K., Xi, K., Ratia, K., Santarsiero, B.D., Fu, W., Harcourt, B.H., Rota, P.A., Baker, S.C., Johnson, M.E., Mesecar, A.D. J. Med. Chem. (2005) [Pubmed]
  16. Identification and characterization of a novel protein inhibitor of type 1 protein phosphatase. Shirato, H., Shima, H., Sakashita, G., Nakano, T., Ito, M., Lee, E.Y., Kikuchi, K. Biochemistry (2000) [Pubmed]
  17. c-Src-dependent cross-talk between CEACAM6 and alphavbeta3 integrin enhances pancreatic adenocarcinoma cell adhesion to extracellular matrix components. Duxbury, M.S., Ito, H., Ashley, S.W., Whang, E.E. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  18. Protein structures of common bean (Phaseolus vulgaris) alpha-amylase inhibitors. Lee, S.C., Gepts, P.L., Whitaker, J.R. J. Agric. Food Chem. (2002) [Pubmed]
  19. Distinct pathways regulate expression of cardiac electrical and mechanical junction proteins in response to stretch. Yamada, K., Green, K.G., Samarel, A.M., Saffitz, J.E. Circ. Res. (2005) [Pubmed]
  20. Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils. Ryckman, C., Gilbert, C., de Médicis, R., Lussier, A., Vandal, K., Tessier, P.A. J. Leukoc. Biol. (2004) [Pubmed]
  21. Tyrosine phosphorylation of vascular endothelial cadherin and the regulation of microvascular permeability. Nwariaku, F.E., Liu, Z., Zhu, X., Turnage, R.H., Sarosi, G.A., Terada, L.S. Surgery (2002) [Pubmed]
  22. The Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases. Tatton, L., Morley, G.M., Chopra, R., Khwaja, A. J. Biol. Chem. (2003) [Pubmed]
  23. Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes. Das, S., Powell, S.R., Wang, P., Divald, A., Nesaretnam, K., Tosaki, A., Cordis, G.A., Maulik, N., Das, D.K. Am. J. Physiol. Heart Circ. Physiol. (2005) [Pubmed]
  24. Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats. Guillem, K., Vouillac, C., Azar, M.R., Parsons, L.H., Koob, G.F., Cador, M., Stinus, L. Eur. J. Neurosci. (2006) [Pubmed]
  25. 3-Hydroxyanthranilic acid accumulation following administration of the 3-hydroxyanthranilic acid 3,4-dioxygenase inhibitor NCR-631. Fornstedt-Wallin, B., Lundström, J., Fredriksson, G., Schwarcz, R., Luthman, J. Eur. J. Pharmacol. (1999) [Pubmed]
  26. Species differences in anticoagulant and anti-Xa activity of DX-9065a, a highly selective factor Xa inhibitor. Hara, T., Yokoyama, A., Morishima, Y., Kunitada, S. Thromb. Res. (1995) [Pubmed]
  27. Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. Bryant, H.E., Helleday, T. Nucleic Acids Res. (2006) [Pubmed]
  28. Interaction of rofecoxib and celecoxib with warfarin. Schaefer, M.G., Plowman, B.K., Morreale, A.P., Egan, M. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. (2003) [Pubmed]
  29. Formation of a photoreversible phycocyanobilin-apophytochrome adduct in vitro. Elich, T.D., Lagarias, J.C. J. Biol. Chem. (1989) [Pubmed]
  30. Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors. Terasaka, T., Okumura, H., Tsuji, K., Kato, T., Nakanishi, I., Kinoshita, T., Kato, Y., Kuno, M., Seki, N., Naoe, Y., Inoue, T., Tanaka, K., Nakamura, K. J. Med. Chem. (2004) [Pubmed]
  31. Tyrosine phosphorylation of the delta-opioid receptor. Evidence for its role in mitogen-activated protein kinase activation and receptor internalization*. Kramer, H.K., Andria, M.L., Esposito, D.H., Simon, E.J. Biochem. Pharmacol. (2000) [Pubmed]
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