WordNet
- limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
- control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
- limit the range or extent of; "Contact between the young was inhibited by strict social customs"
- a substance that retards or stops an activity
- an enzyme that catalyzes the conversion of a proenzyme to an active enzyme
- an amino acid found in most proteins; a precursor of several hormones
- the basic unit of money in Papua New Guinea
PrepTutorEJDIC
- 〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
- 抑制する人(物) / 化学反応抑制剤
Wikipedia preview
出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/09/17 11:45:20」(JST)
[Wiki en表示]
Crystal structure of the second generation Bcr-Abl tyrosine-kinase inhibitor nilotinib (red) in complex with an Abl kinase domain (blue). Nilotinib is used to treat chronic myelogenous leukemia (CML), a hematological malignancy.
A tyrosine-kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation). TKIs are typically used as anti-cancer drugs.
They are also called tyrphostins, the short name for “tyrosine phosphorylation inhibitor”, originally coined in a 1988 publication,[1] which was the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor (EGFR).
The 1988 study was the first demonstration of a systematic search and discovery of small molecular weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2.[2][3]
Contents
- 1 Development of drugs
- 2 Mechanisms
- 3 See also
- 4 References
Development of drugs[edit source | edit]
Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumor agents and anti-leukemic agents.[4][5] Based on this work imatinib was developed against chronic myelogenous leukemia (CML)[6] and later gefitinib and erlotinib aiming at the EGF receptor. Sunitinib, an inhibitor of the receptors for FGF, PDGF and VEGF is also based on early studies on TKIs aiming at VEGF receptors.[7] It is estimated that about 30% of the current effort of the pharmaceutical industry is devoted to the development of protein kinase inhibitors, especially TKIs[citation needed].
Mechanisms[edit source | edit]
TKIs operate by four different mechanisms: they can compete with adenosine triphosphate (ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change.[8] Signal transduction therapy can in principle also apply for non-cancer proliferative diseases and for inflammatory conditions.[9] Until now TKIs have not been developed for the treatment of such conditions.
See also[edit source | edit]
- Bcr-Abl tyrosine-kinase inhibitor
- Protein kinase inhibitor
References[edit source | edit]
- ^ Yaish P, Gazit A, Gilon C, Levitzki A. (1988). "Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors.". Science 242 (4880): 933–935. doi:10.1126/science.3263702. PMID 3263702.
- ^ Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C, Levitzki A. (1991). "Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases". J Med Chem 34 (6): 1896–907. doi:10.1021/jm00110a022. PMID 1676428.
- ^ Osherov N, Gazit A, Gilon C, Levitzki A. (1993). "Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins". J Biol Chem 268 (15): 11134–42. PMID 8098709.
- ^ Anafi M, Gazit A, Zehavi A, Ben-Neriah Y, Levitzki A. (1993). "Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate". Blood 82 (12): 3524–9. PMID 7505115.
- ^ Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM. (1996). "Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor". Nature 379 (6566): 645–8. doi:10.1038/379645a0. PMID 8628398.
- ^ Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB. (1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat Med 2 (5): 561–6. doi:10.1038/nm0596-561. PMID 8616716.
- ^ Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK. (1996). "Flk-1 as a target for tumor growth inhibition". Cancer Res. 56 (15): 3540–5. PMID 8758924.
- ^ Posner I, Engel M, Gazit A, Levitzki A. (1994). "Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program". Mol Pharmacol. 45 (4): 673–83. PMID 8183246.
- ^ Levitzki A, Mishani E. (2006). "Tyrphostins and other tyrosine kinase inhibitors". Annu Rev Biochem 75: 93–109. doi:10.1146/annurev.biochem.75.103004.142657. PMID 16756486.
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Targeted therapy / extracellular chemotherapeutic agents/antineoplastic agents (L01)
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| CI monoclonal antibodies ("-mab") |
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Receptor tyrosine kinase
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- ErbB: HER1/EGFR (Cetuximab
- Panitumumab)
- HER2/neu (Trastuzumab
- Trastuzumab emtansine)
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Others for solid tumors
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- EpCAM (Catumaxomab
- Edrecolomab)
- VEGF-A (Bevacizumab)
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Leukemia/lymphoma
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- lymphoid: CD20 (Ibritumomab
- Ofatumumab
- Rituximab
- Tositumomab), CD30 (Brentuximab), CD52 (Alemtuzumab)
myeloid: CD33 (Gemtuzumab)
|
|
|
| Tyrosine-kinase inhibitors ("-nib") |
|
Receptor tyrosine kinase
|
- ErbB: HER1/EGFR (Erlotinib
- Gefitinib
- Vandetanib)
- HER1/EGFR and HER2/neu (Afatinib
- Lapatinib
- Neratinib)
- RTK class III: C-kit and PDGFR (Axitinib
- Masitinib
- Pazopanib
- Sunitinib
- Sorafenib
- Toceranib)
- FLT3 (Lestaurtinib)
- VEGFR (Axitinib
- Cediranib
- Pazopanib
- Regorafenib
- Semaxanib
- Sorafenib
- Sunitinib
- Toceranib
- Vandetanib)
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|
|
Non-receptor
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- bcr-abl (Imatinib
- Dasatinib
- Nilotinib
- Ponatinib)
- Janus kinase (Lestaurtinib
- Ruxolitinib)
EML4-ALK (Crizotinib)
RET inhibitors: Vandetanib (Also VEGFR and EGFR).
c-MET inhibitor: Cabozantinib (Also VEGFR2).
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|
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| Other |
- fusion protein against VEGF (Aflibercept)
- proapoptotic peptide against ANXA2 and prohibitin (Adipotide)
- exotoxin against IL-2 (Denileukin diftitox)
- mTOR inhibitors (Everolimus
- Temsirolimus)
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Pharmacology: enzyme inhibition
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| Class |
- Competitive inhibition
- Uncompetitive inhibition
- Non-competitive inhibition
- Suicide inhibition
- Mixed inhibition
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|
| Substrate |
| Oxidoreductase (EC 1) |
- 1.1 Aldose reductase
- HMG-CoA reductase
- 1.5 Dihydrofolate reductase
- 1.17 Xanthine oxidase
- Ribonucleotide reductase
|
|
| Transferase (EC 2) |
- 2.1 COMT
- Thymidylate synthase
- 2.5 Dihydropteroate synthetase
- Farnesyltransferase
- 2.7 Nucleotidyltransferase
- Integrase
- Reverse transcriptase
- Protein kinase
|
|
| Hydrolase (EC 3) |
- 3.1 Phosphodiesterase
- Acetylcholinesterase
- Ribonuclease
- 3.2 Polygalacturonase
- Neuraminidase
- Alpha-glucosidase
- 3.4 Protease: Exopeptidase
- Dipeptidyl peptidase-4
- ACE
- Endopeptidase
- Trypsin
- Renin
- Matrix metalloproteinase
- 3.5 Histone deacetylase
- Beta-lactamase
|
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| Lyase (EC 4) |
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UpToDate Contents
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English Journal
- mTOR inhibitors in advanced breast cancer: Ready for prime time?
- Martin LA, André F, Campone M, Bachelot T, Jerusalem G.SourceBreakthrough Breast Cancer Centre, Institute of Cancer Research, London, United Kingdom. Electronic address: Lesley-ann.marti@icr.ac.uk.
- Cancer treatment reviews.Cancer Treat Rev.2013 Nov;39(7):742-52. doi: 10.1016/j.ctrv.2013.02.005. Epub 2013 Apr 1.
- Current therapeutic approaches for advanced breast cancer frequently target receptors mediating cell survival and proliferation, such as the estrogen receptor and/or progesterone receptor and human epidermal growth factor receptor-2. Although these approaches are effective for many patients, treatme
- PMID 23557794
- Risk of hematologic toxicities in cancer patients treated with sunitinib: A systematic review and meta-analysis.
- Funakoshi T, Latif A, Galsky MD.SourceDepartment of Medicine, Beth Israel Medical Center, University Hospital and Manhattan Campus for the Albert Einstein College of Medicine, New York, USA. Electronic address: tfunakoshi@chpnet.org.
- Cancer treatment reviews.Cancer Treat Rev.2013 Nov;39(7):818-30. doi: 10.1016/j.ctrv.2013.01.004. Epub 2013 Feb 28.
- BACKGROUND: The incidence and risk of unique toxicities associated with a multi-targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We
- PMID 23455076
- The emerging role of MET/HGF inhibitors in oncology.
- Scagliotti GV, Novello S, von Pawel J.SourceDepartment of Oncology, University of Turin, San Luigi Hospital, Regione Gonzale 10, 10043 Orbassano, Turin, Italy. Electronic address: giorgio.scagliotti@unito.it.
- Cancer treatment reviews.Cancer Treat Rev.2013 Nov;39(7):793-801. doi: 10.1016/j.ctrv.2013.02.001. Epub 2013 Feb 28.
- The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in man
- PMID 23453860
Japanese Journal
- Met Kinase Inhibitor E7050 Reverses Three Different Mechanisms of Hepatocyte Growth Factor-induced Tyrosine Kinase Inhibitor Resistance in EGFR Mutant Lung Cancer
- Wang Wei,Li Qi,Takeuchi Shinji,Yamada Tadaaki,Koizumi Hitomi,Nakamura Takahiro,Matsumoto Kunio,Mukaida Naofumi,Nishioka Yasuhiko,Sone Saburo,Nakagawa Takayuki,Uenaka Toshimitsu,Yano Seiji
- Clinical Cancer Research xx(xx), xxxx-xxxx, 2012-02-08
- … PURPOSE: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and the downstream PI3K/Akt pathway. …
- NAID 120003830985
- Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation.
- Togashi Yosuke,Masago Katsuhiro,Fukudo Masahide,Tsuchido Yasuhiro,Okuda Chiyuki,Kim Young Hak,Ikemi Yasuaki,Sakamori Yuichi,Mio Tadashi,Katsura Toshiya,Mishima Michiaki
- Cancer chemotherapy and pharmacology 68(4), 1089-1092, 2011-10
- Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. We describe a Jap …
- NAID 120003534363
Related Links
- A tyrosine-kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a ...
- Hence, protein kinase inhibitors can be subdivided or characterised by the amino acids whose phosphorylation is inhibited: most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine, and a number (dual-specificity ...
Related Pictures
★リンクテーブル★
[★]
- 英
- tyrosine kinase inhibitor
- 関
- チロシンキナーゼ阻害薬
[★]
- 英
- tyrosine kinase inhibitor
- 関
- チロシンキナーゼ阻害剤
[★]
チロシンキナーゼ抑制剤
[★]
- 関
- abrogate、block、depress、depression、deter、inhibition、interdict、prevent、prevention、repress、repression、restrain、restraint、suppress、suppression
[★]
- 関
- blocker、depressant、suppressant
[★]
キナーゼ カイネース リン酸化酵素 phosphoenzyme phosphotransferase
[★]