WordNet

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

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抑制する人(物) / 化学反応抑制剤

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/25 18:24:35」(JST)

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A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that add a phosphate (PO₄) group to a protein or other organic molecule. Phosphate groups can turn a protein off.

The phosphate groups are usually added to the serine, threonine, or tyrosine amino acid on the protein. 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 kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.^{[citation needed]}

Phosphorylation is a necessary step in some cancers and inflammatory diseases. Inhibiting the protein kinases, and therefore the phosphorylation, can treat these diseases. Therefore, protein kinase inhibitors are used as drugs.

Clinical use[edit]

Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation.^{[citation needed]} The novel kinase inhibitor PLX5568 is currently in clinical trials for treatment of polycystic kidney disease as well as pain.^[1]

Some of the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases.^[2] The effectiveness of kinase inhibitors on various cancers can vary from patient to patient.^[3]

Examples[edit]

Currently there are several drugs launched or in development that target protein kinases and the receptors that activate them:

Name	Target	Company	Class	FDA approval
Afatinib	EGFR/ErbB2	Boehringer Ingelheim	Small molecule	2013 Non-small cell lung cancer
Axitinib	VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-KIT	Pfizer	Small molecule	2012 Renal cell carcinoma
Bevacizumab	VEGF	Genentech	Monoclonal antibody	2004 Colorectal
Bosutinib	BcrAbl /SRC	Pfizer	Small molecule	2012 Chronic myelogenous leukemia
Cetuximab	ErbB1	Imclone/BMS	Monoclonal antibody	2006 Mar (SCCHN)
Crizotinib	ALK/Met	Pfizer	Small molecule	2011 Aug (NSCLC with Alk mutation)
Dasatinib	multiple targets	BMS	Small molecule	2006
Erlotinib	ErbB1	Genentech	Small molecule	2005 Nov ?
Fostamatinib	Syk	Rigel Pharmaceuticals/AstraZeneca	Small molecule	Not yet^[4]
Gefitinib	EGFR	AstraZeneca	Small molecule	2003
Imatinib	Bcr-Abl	Novartis	Small molecule	2001 (CML), 2002 (GIST) ^[5]
Lapatinib	ErbB1/ErbB2	GSK	Small molecule	2007 (HER2+ Breast)
Lenvatinib	VEGFR2/VEGFR2	Eisai Co.	Small molecule	Not yet
Mubritinib	?	Takeda	Small molecule	Not yet, possibly abandoned
Nilotinib	Bcr-Abl	Novartis	Small molecule	2007
Panitumumab	EGFR	Amgen	Monoclonal antibody	2006
Pazopanib	VEGFR2/PDGFR/c-kit	GlaxoSmithKline	Small molecule	2009 (RCC)
Pegaptanib	VEGF	OSI/Pfizer	RNA Aptamer	2004 (AMD)
Ranibizumab	VEGF	Genentech	Monoclonal antibody	2006 (AMD)
Ruxolitinib	JAK	Incyte	Small molecule	2011 (Myelofibrosis)
Sorafenib	multiple targets	Onyx/Bayer	Small molecule	2005 Dec (kidney)
Sunitinib	multiple targets	SUGEN/Pfizer	Small molecule	2006 Jan (RCC & GIST)
SU6656	multiple targets	SUGEN	Small molecule	2000 Jan (RCC & GIST)
Trastuzumab	Erb2	Genentech	Monoclonal antibody	1998 (HER2+ breast cancer)
Tofacitinib	JAK	Pfizer	Small molecule	2012 Nov (RA)
Vandetanib	RET/VEGFR/EGFR	AstraZeneca	Small molecule	No, submission withdrawn Oct09 [1]
Vemurafenib	BRAF	Roche	Small molecule	2011 Aug Melanoma

References[edit]

^ "Plexxikon Initiates Phase 1 Trial for PLX5568".
^ "Definition of tyrosine kinase inhibitor - NCI Dictionary of Cancer Terms".
^ Jänne, Pasi A.; Gray, Nathanael; Settleman, Jeff (2009). "Factors underlying sensitivity of cancers to small-molecule kinase inhibitors". Nature Reviews Drug Discovery 8 (9): 709–23. doi:10.1038/nrd2871. PMID 19629074.
^ Bajpai, M (2009). "Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases". IDrugs 12 (3): 174–85. PMID 19333898.
^ "FDA Grants Imatinib (Gleevec) Full Approval for Adjuvant Treatment of GIST".

External links[edit]

Protein kinase inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
IC50 values for common inhibitors
"Table 1: Chemical structures and known kinase targets for clinically approved kinase inhibitors". in Jänne, Pasi A.; Gray, Nathanael; Settleman, Jeff (2009). "Factors underlying sensitivity of cancers to small-molecule kinase inhibitors". Nature Reviews Drug Discovery 8 (9): 709–23. doi:10.1038/nrd2871. PMID 19629074.

UpToDate Contents

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1. 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤の臨床使用 clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia
2. 血管新生阻害剤の概要 overview of angiogenesis inhibitors
3. 慢性骨髄性白血病の治療の概要 overview of the treatment of chronic myeloid leukemia
4. 分子標的薬である血管新生阻害剤の毒性：心血管系以外への影響 toxicity of molecularly targeted antiangiogenic agents non cardiovascular effects
5. 進行消化管間質腫瘍に対するチロシンキナーゼ阻害剤療法 tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors

English Journal

ALK inhibitors in the treatment of advanced NSCLC.

Gridelli C, Peters S, Sgambato A, Casaluce F, Adjei AA, Ciardiello F.Author information Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy. Electronic address: cgridelli@libero.it.AbstractPharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule-associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in-class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC.
Cancer treatment reviews.Cancer Treat Rev.2014 Mar;40(2):300-6. doi: 10.1016/j.ctrv.2013.07.002. Epub 2013 Aug 7.
Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or m
PMID 23931927

Nitric Oxide Regulation of Na, K-ATPase Activity in Ocular Ciliary Epithelium Involves Src Family Kinase.

Shahidullah M, Mandal A, Wei G, Delamere NA.Author information Department of Physiology, University of Arizona, Tucson, Arizona.AbstractThe nitric oxide (NO) donor sodium nitroprusside (SNP) is known to reduce aqueous humor (AH) secretion in the isolated porcine eye. Previously, SNP was found to inhibit Na,K-ATPase activity in nonpigmented ciliary epithelium (NPE), AH-secreting cells, through a cGMP/protein kinase G (PKG)-mediated pathway. Here we show Src family kinase (SFK) activation in the Na,K-ATPase activity response to SNP. Ouabain-sensitive (86) Rb uptake was reduced by >35% in cultured NPE cells exposed to SNP (100 µM) or exogenously added cGMP (8-Br-cGMP) (100 µM) and the SFK inhibitor PP2 (10 µM) prevented the response. Ouabain-sensitive ATP hydrolysis was reduced by ∼40% in samples detected in material obtained from SNP- and 8-Br-cGMP-treated cells following homogenization, pointing to an intrinsic change of Na,K-ATPase activity. Tyrosine-10 phosphorylation of Na,K-ATPase α1 subunit was detected in SNP and L-arginine-treated cells and the response prevented by PP2. SNP elicited an increase in cell cGMP. Cells exposed to 8-Br-cGMP displayed SFK activation (phosphorylation) and inhibition of both ouabain-sensitive (86) Rb uptake and Na,K-ATPase activity that was prevented by PP2. SFK activation, which also occurred in SNP-treated cells, was suppressed by inhibitors of soluble guanylate cyclase (ODQ; 10 µM) and PKG (KT5823; 1 µM). SNP and 8-Br-cGMP also increased phosphorylation of ERK1/2 and p38 MAPK and the response prevented by PP2. However, U0126 did not prevent SNP or 8-Br-cGMP-induced inhibition of Na,K-ATPase activity. Taken together, the results suggest that NO activates guanylate cyclase to cause a rise in cGMP and subsequent PKG-dependent SFK activation. Inhibition of Na,K-ATPase activity depends on SFK activation. J. Cell. Physiol. 229: 343-352, 2014. © 2013 Wiley Periodicals, Inc.
Journal of cellular physiology.J Cell Physiol.2014 Mar;229(3):343-52. doi: 10.1002/jcp.24454.
The nitric oxide (NO) donor sodium nitroprusside (SNP) is known to reduce aqueous humor (AH) secretion in the isolated porcine eye. Previously, SNP was found to inhibit Na,K-ATPase activity in nonpigmented ciliary epithelium (NPE), AH-secreting cells, through a cGMP/protein kinase G (PKG)-mediated p
PMID 24037816

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins.

Remon J, Morán T, Majem M, Reguart N, Dalmau E, Márquez-Medina D, Lianes P.Author information Medical Oncology Department, Hospital de Mataró, Carretera de la Cirera, s/n, 08304 Mataró, Barcelona, Spain. Electronic address: jremon@csdm.cat.AbstractThe discovery of mutated oncogenes has opened up a new era for the development of more effective treatments for non-small cell lung cancer patients (NSCLC) harbouring EGFR mutations. However, patients with EGFR-activating mutation ultimately develop acquired resistance (AR). Several studies have identified some of the mechanisms involved in the development of AR to EGFR tyrosine kinase inhibitors (TKI) that can be potential therapeutic strategies, although in up to 30% of cases, the underlying mechanism of AR are still unexplained. In this review we aim to summarize the main mechanisms of AR to EGFR TKI and some clinical strategies that can be used in the daily clinical practice to overcome this resistance and try to prolong the outcomes in this subgroup of patients.
Cancer treatment reviews.Cancer Treat Rev.2014 Feb;40(1):93-101. doi: 10.1016/j.ctrv.2013.06.002. Epub 2013 Jul 3.
The discovery of mutated oncogenes has opened up a new era for the development of more effective treatments for non-small cell lung cancer patients (NSCLC) harbouring EGFR mutations. However, patients with EGFR-activating mutation ultimately develop acquired resistance (AR). Several studies have ide
PMID 23829935

Japanese Journal

スニチニブ投与にて比較的長期予後が得られた転移性集合管癌の1例

竹島徹平,村真波,関口善吉,滝沢明利,土屋ふとし
泌尿器科紀要 = Acta urologica Japonica 60(3), 133-136, 2014-03
… It would be worthwhile to prospectively evaluate the antitumor activity of tyrosine kinase inhibitors against metastatic CDC. …
NAID 120005439497

チロシンキナーゼ阻害剤投与中に消化管出血をきたした慢性骨髄性白血病

斉藤誠,泉山康,盛暁生 [他]
臨床血液 55(1), 130-132, 2014-01
NAID 40019962706

慢性骨髄性白血病治療の現状 (特集造血器疾患 : 最新の冶療戦略(骨髄系疾患))

中山一隆,猪口孝一
臨床血液 55(1), 42-55, 2014-01
NAID 40019962375

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