Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/09/10 00:06:11」(JST)

wiki en

Crizotinib (trade name Xalkori,^[1] Pfizer) is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor,^[2]^[3]^[4] approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.^[5]

Mechanism of action

Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2^[6]

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 ('echinoderm microtubule-associated protein-like 4') and ALK ('anaplastic lymphoma kinase'), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype.^[7] The kinase activity of the fusion protein is inhibited by crizotinib.^[7] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene.^[7]^[8] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.^[9]^[10]

ALK mutations are thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.^[11]

Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.^[12]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.^[12]^[13] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.^[14]

Approvals and indications

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.^[1] Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the U.S. Food and Drug Administration approved crizotinib in ROS1-positive non-small cell lung cancer.^[15]

Clinical trials

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.^[8]^[9] Tumors shrank at least 30% in 57% of people treated.^[9] ^[16] Most had adenocarcinoma, and had never smoked or were former smokers.^[8] They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy.^[8]^[17] They were given 250 mg crizotinib twice daily for a median duration of six months.^[8] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.^[17] Some responses to crizotinib have lasted up to 15 months.^[17]

A phase 3 trial, PROFILE 1007,^[18] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.^[5]^[10]^[19] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.^[10]

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,^[12] and neuroblastoma.^[20]

References

^ ^a ^b "FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer". U.S. Food and Drug Administration.
^ Forde PM, Rudin CM (2012). "Crizotinib in the treatment of non-small-cell lung cancer". Expert Opin Pharmacother. 13 (8): 1195–201. doi:10.1517/14656566.2012.688029. PMID 22594847.
^ Roberts PJ (2013). "Clinical use of crizotinib for the treatment of non-small cell lung cancer". Biologics. 7: 91–101. doi:10.2147/BTT.S29026. PMC 3643289. PMID 23671386.
^ Sahu A, Prabhash K, Noronha V, Joshi A, Desai S (2013). "Crizotinib: A comprehensive review". South Asian J Cancer. 2 (2): 91–7. doi:10.4103/2278-330X.110506. PMC 3876666. PMID 24455567.
^ ^a ^b Clinical trial number NCT00932451 for "An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov
^ Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (2011). "Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)". J. Med. Chem. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID 21812414.
^ ^a ^b ^c "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07.
^ ^a ^b ^c ^d ^e "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07.
^ ^a ^b ^c Winslow, Ron (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. Retrieved 2010-06-07.
^ ^a ^b ^c "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (PDF) (Press release). Pfizer Oncology. 2010-05-20. Retrieved 2010-06-07.
^ Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. doi:10.1038/onc.2009.518. PMID 20101209.
^ ^a ^b ^c Clinical trial number NCT00585195 for "A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer" at ClinicalTrials.gov
^ Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007). "Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma". Mol. Cancer Ther. 6 (12 Pt 1): 3314–22. doi:10.1158/1535-7163.MCT-07-0365. PMID 18089725.
^ Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG (2007). "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms". Cancer Res. 67 (9): 4408–17. doi:10.1158/0008-5472.CAN-06-4443. PMID 17483355.
^ "NICE backs Pfizer's Xalkori after squeezing out a new discount - FiercePharma".
^ Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC". NB Fig 1.
^ ^a ^b ^c "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. Retrieved 2010-06-07.
^ "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling" (PDF). Fact Sheet. Pfizer.
^ Clinical trial number NCT00932893 for "An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov
^ Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP (2009). "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066". J Clin Oncol. 27 (15s. suppl; abstr 10008b).

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 未分化リンパ腫キナーゼ（ALK）融合癌遺伝子陽性非小細胞肺癌 anaplastic lymphoma kinase alk fusion oncogene positive non small cell lung cancer
2. 進行非小細胞肺癌に対する遺伝子型による個別治療 personalized genotype directed therapy for advanced non small cell lung cancer
3. 抗腫瘍療法関連肺毒性：分子標的剤 pulmonary toxicity associated with antineoplastic therapy molecularly targeted agents
4. 小児の非ホジキンリンパ腫の概要 overview of pediatric non hodgkin lymphoma
5. アントラサイクリン系以外の癌化学療法剤の心毒性 cardiotoxicity of nonanthracycline cancer chemotherapy agents

English Journal

Fluorescence spectroscopic and molecular docking studies of the binding interaction between the new anaplastic lymphoma kinase inhibitor crizotinib and bovine serum albumin.

Abdelhameed AS1, Alanazi AM2, Bakheit AH2, Darwish HW3, Ghabbour HA4, Darwish IA2.
Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.Spectrochim Acta A Mol Biomol Spectrosc.2017 Jan 15;171:174-182. doi: 10.1016/j.saa.2016.08.005. Epub 2016 Aug 5.
Binding of the recently introduced anti-cancer drug, crizotinib (CRB) with the bovine serum albumin (BSA) was comprehensively studied with the aid of fluorescence and UV-Vis spectroscopic as well as molecular docking techniques. The collective results of the study under the simulated physiological c
PMID 27526341

An UPLC-MS/MS method for the quantitation of alectinib in rat plasma.

Huang XX1, Li YX1, Li XY1, Hu XX1, Tang PF1, Hu GX2.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2017 Jan 5;132:227-231. doi: 10.1016/j.jpba.2016.10.010. Epub 2016 Oct 14.
Currently, crizotinib is the first generation drug, which has been used in the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). However, more and more patients are found in crizotinib-resistance. In the last year, alectinib has been approved for treatment of patients with crizotinib-r
PMID 27768922

Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

De Rosa V1, Iommelli F1, Monti M2, Mainolfi CG2, Fonti R1, Del Vecchio S3.
EJNMMI research.EJNMMI Res.2016 Dec;6(1):74. Epub 2016 Oct 10.
BACKGROUND: The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of 18F-f
PMID 27726115

Japanese Journal

外科的に脳転移を診断しアレクチニブが著効したALK陽性肺癌の1例

肺癌 57(1), 23-28, 2017
NAID 130005398641

症例中枢神経系転移をきたしたクリゾチニブ耐性ALK陽性肺癌にアレクチニブが臨床的に有効であった4例

日本呼吸器学会誌 = Annals of the Japanese Respiratory Society 5(4), 184-188, 2016-07-10
NAID 40020912709

ROS-1,RET阻害剤の開発状況 (特集肺癌分子標的治療・免疫療法の最前線)

呼吸器内科 = Respiratory medicine 30(1), 42-47, 2016-07
NAID 40020920034

Related Pictures

Crizotinib Cancer Medicines - Dacogen Exporter from Nagpur Variants on a Theme: A Biomarker of Crizotinib Response in ALK-Positive Non–Small FDA OKs Crizotinib (Xalkori) for ROS-1-Mutated Lung Cancer New Study Manages To Prevent Neuroblastoma Resistance To Crizotinib - Doctor Tipster Crizotinib - Crizotinib - All - Small Molecules Crizotinib Shows Promise for Childhood Cancers - National Cancer Institute Crizalk 250Mg: Crizalk 250Mg Capsules | Crizotinib 250Mg Capsules Reasonable Price

★リンクテーブル★

リンク元

「クリゾチニブ」

Crizotinib
Systematic (IUPAC) name
	3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Clinical data
Trade names	Xalkori
MedlinePlus	a612018
License data	EU EMA: Xalkori; US FDA: Crizotinib;
Pregnancy; category	AU: D; US: D (Evidence of risk); ;
Routes of; administration	Oral
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Bioavailability	43%
Protein binding	91%
Metabolism	Hepatic (CYP3A4/CYP3A5-mediated)
Biological half-life	42 hours
Excretion	Faeces (63%), urine (22%)
Identifiers
CAS Number	877399-52-5
ATC code	L01XE16 (WHO)
PubChem	CID 11626560
IUPHAR/BPS	4903
DrugBank	DB08700
ChemSpider	9801307
UNII	53AH36668S
KEGG	D09731
ChEBI	CHEBI:64310
ChEMBL	CHEMBL601719
Synonyms	PF-02341066; 1066
PDB ligand ID	VGH (PDBe, RCSB PDB)
Chemical data
Formula	C21H22Cl2FN5O
Molar mass	450.337 g/mol
	SMILES C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl ;
	InChI InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1 ; Key:KTEIFNKAUNYNJU-GFCCVEGCSA-N ;
(what is this?) (verify)

　　[★]

英: crizotinib
商: ザーコリ
関: その他の腫瘍用薬

[Xalkori20110826-1] "FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer". U.S. Food and Drug Administration.

[pmid22594847-2] Forde PM, Rudin CM (2012). "Crizotinib in the treatment of non-small-cell lung cancer". Expert Opin Pharmacother. 13 (8): 1195–201. doi:10.1517/14656566.2012.688029. PMID 22594847.

[pmid23671386-3] Roberts PJ (2013). "Clinical use of crizotinib for the treatment of non-small cell lung cancer". Biologics. 7: 91–101. doi:10.2147/BTT.S29026. PMC 3643289. PMID 23671386.

[pmid24455567-4] Sahu A, Prabhash K, Noronha V, Joshi A, Desai S (2013). "Crizotinib: A comprehensive review". South Asian J Cancer. 2 (2): 91–7. doi:10.4103/2278-330X.110506. PMC 3876666. PMID 24455567.

[ClinicalTrial1-5] Clinical trial number NCT00932451 for "An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov

[pmid21812414-6] Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (2011). "Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)". J. Med. Chem. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID 21812414.

[CME-7] "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07.

[HemOncToday-8] "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07.

[WSJ-9] Winslow, Ron (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. Retrieved 2010-06-07.

[PfizerPress-10] "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (PDF) (Press release). Pfizer Oncology. 2010-05-20. Retrieved 2010-06-07.

[Janoueix-11] Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. doi:10.1038/onc.2009.518. PMID 20101209.

[TrialNCT00585195-12] Clinical trial number NCT00585195 for "A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer" at ClinicalTrials.gov

[Christensen_2007-13] Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007). "Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma". Mol. Cancer Ther. 6 (12 Pt 1): 3314–22. doi:10.1158/1535-7163.MCT-07-0365. PMID 18089725.

[Zou_2007-14] Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG (2007). "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms". Cancer Res. 67 (9): 4408–17. doi:10.1158/0008-5472.CAN-06-4443. PMID 17483355.

[15] "NICE backs Pfizer's Xalkori after squeezing out a new discount - FiercePharma".

[16] Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC". NB Fig 1.

[MSNBC-17] "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. Retrieved 2010-06-07.

[urlwww.pfizer.com-18] "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling" (PDF). Fact Sheet. Pfizer.

[ClinicalTrial2-19] Clinical trial number NCT00932893 for "An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov

[NeuroblastomaTrial-20] Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP (2009). "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066". J Clin Oncol. 27 (15s. suppl; abstr 10008b).

匿名

検索

案内

案内

crizotinib