同: PTK-787

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/11/29 14:17:58」(JST)

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Vatalanib (INN, codenamed PTK787 or PTK/ZK) is a small molecule protein kinase inhibitor that inhibits angiogenesis. It is being studied as a possible treatment for several types of cancer, particularly cancer that is at an advanced stage or has not responded to chemotherapy. Vatalanib is orally active, that is, it is effective when taken by mouth.

Vatalanib is being developed by Bayer Schering and Novartis. It inhibits all known VEGF receptors, as well as platelet-derived growth factor receptor-beta and c-kit, but is most selective for VEGFR-2.^[1]^[2]^[3]^[4]

Development

Vatalanib was discovered through high-throughput screening.^[2] It has been extensively investigated in Phase I, II and III clinical trials.^[1]^[4] Two large, randomized controlled Phase III trials have studied the effect of adding vatalanib to the FOLFOX chemotherapy regimen in people with metastatic colorectal cancer: CONFIRM-1, whose participants had not yet received any treatment for their cancer; and CONFIRM-2, in which participants had received first-line treatment with irinotecan and fluoropyrimidines. Vatalanib produced no significant improvement in overall survival (the primary endpoint of the studies), although it did significantly increase progression-free survival in CONFIRM-2.^[4] Both trials found that progression-free survival was improved in people with high levels of lactate dehydrogenase, an enzyme used as a marker of tissue breakdown; the reasons for and implications of this difference are still unclear.^[4]^[5]

Adverse effects

The adverse effects of vatalanib appear similar to those of other VEGF inhibitors. In the CONFIRM trials, the most common side effects were high blood pressure, gastrointestinal upset (diarrhea, nausea, and vomiting), fatigue, and dizziness.^[4]

References

^ ^a ^b ^c ^d ^e Jost LM, Gschwind HP, Jalava T, et al. (November 2006). "Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients". Drug Metabolism and Disposition. 34 (11): 1817–28. doi:10.1124/dmd.106.009944. PMID 16882767.
^ ^a ^b Mariani SM (2004). "Antiangiogenesis Cocktails -- Stirred or Shaken?: Highlights of the 9th Annual Drug Discovery Technology World Congress; August 8-13, 2004; Boston, Massachusetts". Medscape General Medicine. 6 (4): 21. PMC 1480579. PMID 15775848. Retrieved on October 29, 2008.
^ Wood JM, Bold G, Buchdunger E, et al. (April 2000). "PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration". Cancer Research. 60 (8): 2178–89. PMID 10786682.
^ ^a ^b ^c ^d ^e Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.
^ Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL (March 2007). "Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours". Expert Opin Investig Drugs. 16 (3): 367–79. doi:10.1517/13543784.16.3.367. PMID 17302531.

External links

Ongoing and completed clinical trials of vatalanib at ClinicalTrials.gov (U.S. National Institutes of Health)

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English Journal

Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks.

Achyut BR1, Shankar A1, Iskander AS1, Ara R1, Angara K1, Zeng P1, Knight RA2, Scicli AG3, Arbab AS4.
Cancer letters.Cancer Lett.2015 Dec 28;369(2):416-26. doi: 10.1016/j.canlet.2015.09.004. Epub 2015 Sep 21.
Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BM
PMID 26404753

2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib.

Gohlke BO1, Overkamp T2, Richter A3, Richter A4, Daniel PT5,6,7, Gillissen B8,9, Preissner R10,11.
BMC bioinformatics.BMC Bioinformatics.2015 Sep 24;16:308. doi: 10.1186/s12859-015-0730-x.
BACKGROUND: Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study
PMID 26403354

Vatalanib sensitizes ABCB1 and ABCG2-overexpressing multidrug resistant colon cancer cells to chemotherapy under hypoxia.

To KK1, Poon DC2, Wei Y3, Wang F4, Lin G5, Fu LW6.
Biochemical pharmacology.Biochem Pharmacol.2015 Sep 1;97(1):27-37. doi: 10.1016/j.bcp.2015.06.034. Epub 2015 Jul 20.
Cancer microenvironment is characterized by significantly lower oxygen concentration. This hypoxic condition is known to reduce drug responsiveness to cancer chemotherapy via multiple mechanisms, among which the upregulation of the ATP-binding cassette (ABC) efflux transporters confers resistance to
PMID 26206183

Japanese Journal

A validated assay for the quantitative analysis of vatalanib in human EDTA plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry

LANKHEET A. G.,HILLEBRAND M. J. X.,LANGENBERG M. H. G.,ROSING H.,HUITEMA A. D. R.,VOEST E. E.,SCHELLENS J. H. M.,BEIJNEN J. H.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 877(29), 3625-3630, 2009-11-01
NAID 10028028114

COMPARATIVE VEGF RECEPTOR TYROSINE KINASE MODELING FOR THE DEVELOPMENT OF HIGHLY SPECIFIC INHIBITORS OF TUMOR ANGIOGENESIS

SCHMIDT ULRIKE,AHMED JESSICA,MICHALSKY ELKE,HOEPFNER MICHAEL,PREISSNER ROBERT
Ｇｅｎｏｍｅ　Ｉｎｆｏｒｍａｔｉｃｓ 20, 243-251, 2008
… Here, we describe a protocol starting from an established inhibitor (Vatalanib) with 2D-/3Dsearching and property filtering of the in silico screening hits and the "negative docking approach". …
NAID 130003997527

Related Pictures

Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal Vatalanib Dihydrochloride | CAS 212141-51-0 | SCBT - Santa Cruz Biotechnology Vatalanib Dihydrochloride | ABIN956528 212141-54-3 | Vatalanib | Tetrahedron Vatalanib/PTK787/PTK-787/PTK 787/ZK222584/ZK-222584/ZK 222584/CGP79787/CGP-79787/CGP Vatalanib|VEGFR-1/-2 inhibitor,cell-permeable|CAS# 212141-54-3 Metabolism and Disposition of Vatalanib (PTK787/ZK-222584) in Cancer Patients | Drug

★リンクテーブル★

リンク元	「nib」「血管新生阻害薬」

「nib」

Vatalanib
Clinical data
Pregnancy; category	None assigned;
Routes of; administration	Oral
ATC code	none
Legal status
Legal status	Investigational;
Pharmacokinetic data
Bioavailability	High
Metabolism	Extensive hepatic metabolism (mostly CYP3A4-mediated)
Biological half-life	4.6 ± 1.1 h
Excretion	Fecal and renal
Identifiers
	Systematic (IUPAC) name: N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin- 1-amine
CAS Number	212141-54-3
PubChem (CID)	151194
IUPHAR/BPS	5705
DrugBank	DB04879
ChemSpider	133257
UNII	5DX9U76296
ChEBI	CHEBI:90620
ChEMBL	CHEMBL101253
Chemical and physical data
Formula	C20H15ClN4
Molar mass	346.813 g·mol−1
3D model (Jmol)	Interactive image
	SMILES Clc1ccc(cc1)Nc3nnc(c2c3cccc2)Cc4ccncc4 ;

　　[★]

受容体のリガンド結合部を標的とした小分子化合物。

nib

アキシチニブ axitinib
ボスチニブ bosutinib
ブリバニブ brivanib
カネルチニブ canertinib
セジラニブ cediranib
ダサチニブ dasatinib　チロシンキナーゼ阻害薬　イマチニブ抵抗性の慢性骨髄性白血病、再発又は難治性のフィラデルフィア染色体陽性急性リンパ性白血病
エルロチニブ erlotinib
ゲフィチニブ gefitinib
イマチニブ imatinib　チロシンキナーゼ阻害薬　CML、CKIT(CD117)陽性消化管間質腫瘍、
ラパチニブ lapatinib
レスタウルチニブ lestaurtinib
リニファニブ linifanib
ロナファーニブ lonafarnib
ネラチニブ neratinib
ニブリン nibrin
ニロチニブ nilotinib　チロシンキナーゼ阻害薬　イマチニブ抵抗性の慢性期又は移行期の慢性骨髄性白血病
パゾパニブ pazopanib
ペガプタニブ pegaptanib
ラニビズマブ ranibizumab
セマキシニブ semaxinib
ソラフェニブ sorafenib
スニチニブ sunitinib　VEGFRやPDGFRチロシンキナーゼ阻害薬　イマチニブ抵抗性の消化管間質腫瘍、根治切除不能又は転移性の腎細胞癌
ティピファニブ tipifarnib
バンデタニブ vandetanib
バタラニブ vatalanib

「血管新生阻害薬」

　　[★]

英: angiogenic inhibitor、anti-angiogenic agent
関: 血管新生阻害剤、血管新生抑制因子、血管新生抑制剤、血管新生抑制物質、血管新生抑制薬、抗血管新生薬; 血管内皮増殖因子 VEGF

[show details]

血管新生阻害剤 angiogenesis : 約 77 件
血管新生阻害薬 angiogenesis : 約 83 件

薬理学

抗VEGF抗体

bevacizumab

VEGF阻害薬

sunitinib(SU11248) 受容体キナーゼ阻害薬 -> VEGFR-1, VEGFR-2, PDGFRを阻害
sorafenib -> B-RAF, VEGFR-1, VEGFR-2, PDGFRを阻害
vatalanib(PTK-787)

サリドマイドとレナリドマイド

[Jost-1] Jost LM, Gschwind HP, Jalava T, et al. (November 2006). "Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients". Drug Metabolism and Disposition. 34 (11): 1817–28. doi:10.1124/dmd.106.009944. PMID 16882767.

[Mariani-2] Mariani SM (2004). "Antiangiogenesis Cocktails -- Stirred or Shaken?: Highlights of the 9th Annual Drug Discovery Technology World Congress; August 8-13, 2004; Boston, Massachusetts". Medscape General Medicine. 6 (4): 21. PMC 1480579. PMID 15775848. Retrieved on October 29, 2008.

[Wood-3] Wood JM, Bold G, Buchdunger E, et al. (April 2000). "PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration". Cancer Research. 60 (8): 2178–89. PMID 10786682.

[Los-4] Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.

[5] Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL (March 2007). "Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours". Expert Opin Investig Drugs. 16 (3): 367–79. doi:10.1517/13543784.16.3.367. PMID 17302531.

匿名

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案内

案内

vatalanib