crizotinib indications/contra

Stem definitionDrug idCAS RN
tyrosine kinase inhibitors 4187 877399-52-5

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • crizotinib
  • xalkori
  • PF 02341066
  • PF-02341066
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
  • Molecular weight: 450.34
  • Formula: C21H22Cl2FN5O
  • CLOGP: 4.29
  • LIPINSKI: 0
  • HAC: 6
  • HDO: 2
  • TPSA: 77.99
  • ALOGS: -4.87
  • ROTB: 5

Drug dosage:

None

Approvals:

DateAgencyCompanyOrphan
Oct. 23, 2012 EMA
Aug. 26, 2011 FDA PF PRISM CV

FDA Adverse Event Reporting System

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MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Disease progression 3062.78 55.36 792 3934 31467 3349666
Death 1359.82 55.36 641 4085 151683 3229450
Non-small cell lung cancer 1280.16 55.36 218 4508 895 3380238
Lung neoplasm malignant 1123.46 55.36 252 4474 5076 3376057
Nausea 936.78 55.36 475 4251 129170 3251963
Neoplasm progression 753.95 55.36 182 4544 5062 3376071
Diarrhoea 622.64 55.36 338 4388 104010 3277123
Vomiting 575.34 55.36 305 4421 89226 3291907
Neoplasm malignant 553.64 55.36 157 4569 8240 3372893
Visual impairment 537.89 55.36 173 4553 13973 3367160
Constipation 413.23 55.36 175 4551 30637 3350496
Oedema peripheral 398.10 55.36 176 4550 34185 3346948
Photopsia 366.52 55.36 78 4648 1193 3379940
Interstitial lung disease 289.87 55.36 109 4617 13907 3367226
Fatigue 275.66 55.36 205 4521 107035 3274098
Decreased appetite 260.60 55.36 140 4586 41350 3339783
Pleural effusion 252.26 55.36 107 4619 18672 3362461
Pneumonitis 231.58 55.36 75 4651 6128 3375005
Product use issue 227.63 55.36 95 4631 15906 3365227
Dysgeusia 222.18 55.36 85 4641 11339 3369794
Dysphagia 196.28 55.36 91 4635 19560 3361573
Oedema 194.86 55.36 83 4643 14597 3366536
Oesophagitis 182.55 55.36 54 4672 3257 3377876
Vitreous floaters 173.33 55.36 43 4683 1323 3379810
Pneumonia 152.94 55.36 122 4604 70021 3311112
Pulmonary embolism 146.99 55.36 84 4642 27804 3353329
Vision blurred 145.16 55.36 74 4652 19515 3361618
Renal impairment 138.25 55.36 70 4656 18191 3362942
Dehydration 137.42 55.36 86 4640 33563 3347570
Dyspnoea 136.41 55.36 135 4591 102799 3278334

Pharmacologic Action:

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SourceCodeDescription
ATC L01XE16 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
OTHER ANTINEOPLASTIC AGENTS
Protein kinase inhibitors
CHEBI has role CHEBI:35610 antineoplastic agent
CHEBI has role CHEBI:59163 biomarker
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000190114 Cytochrome P450 3A Inhibitors
FDA MoA N0000020000 Receptor Tyrosine Kinase Inhibitors
FDA MoA N0000182139 Cytochrome P450 2B6 Inhibitors
FDA MoA N0000185503 P-Glycoprotein Inhibitors
FDA MoA N0000191265 Organic Cation Transporter 1 Inhibitors
FDA MoA N0000187061 Organic Cation Transporter 2 Inhibitors
MeSH PA D004791 Enzyme Inhibitors
MeSH PA D047428 Protein Kinase Inhibitors

Drug Use (View source of the data)

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DiseaseRelationSNOMED_IDDOID
Non-small cell lung cancer indication 254637007 DOID:3908

Acid dissociation constants calculated using MoKa v3.0.0

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Dissociation levelDissociation constantType (acidic/basic)
pKa1 9.74 Basic
pKa2 6.14 Basic

Orange Book patent data (new drug applications)

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Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRoutePatent numberPatent expiration datePatent use
200MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL 7825137 May 12, 2027 TREATMENT OF A CANCER MEDIATED BY AN ANAPLASTIC LYMPHOMA KINASE (ALK)
250MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL 7825137 May 12, 2027 TREATMENT OF A CANCER MEDIATED BY AN ANAPLASTIC LYMPHOMA KINASE (ALK)

Orange Book exclusivity data (new drug applications)

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Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRouteExclusivity dateDescription
200MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL Aug. 26, 2018 TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNGCANCER (NSCLC) THAT IS ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE AS DETECTED BY AN FDAAPPROVEDTEST
250MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL Aug. 26, 2018 TREATMENT OF PATIENTS WITH LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNGCANCER (NSCLC) THAT IS ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE AS DETECTED BY AN FDAAPPROVEDTEST
200MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL Sept. 14, 2018 INFORMATION ADDED TO THE LABELING REGARDING PREVIOUSLY UNTREATED ALK-POSITIVE METASTATIC NON SMALL CELL LUNG CANCER (NSCLC)
250MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL Sept. 14, 2018 INFORMATION ADDED TO THE LABELING REGARDING PREVIOUSLY UNTREATED ALK-POSITIVE METASTATIC NON SMALL CELL LUNG CANCER (NSCLC)
200MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL March 11, 2023 TREATMENT OF PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER WHOSE TUMORS ARE ROS-1 POSITIVE.
250MG XALKORI PF PRISM CV N202570 Aug. 26, 2011 RX CAPSULE ORAL March 11, 2023 TREATMENT OF PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER WHOSE TUMORS ARE ROS-1 POSITIVE.

Bioactivity Summary:

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TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
ALK tyrosine kinase receptor Kinase INHIBITOR Ki 9.13 CHEMBL CHEMBL
Hepatocyte growth factor receptor Kinase INHIBITOR Kd 9.26 CHEMBL CHEMBL
Tyrosine-protein kinase ABL1 Kinase Kd 8 CHEMBL
Epidermal growth factor receptor Kinase Kd 5.57 CHEMBL
Serine/threonine-protein kinase DCLK1 Kinase Kd 6.48 CHEMBL
Muscle, skeletal receptor tyrosine-protein kinase Kinase Kd 6.64 CHEMBL
Vascular endothelial growth factor receptor 1 Kinase Kd 5.64 CHEMBL
Proto-oncogene tyrosine-protein kinase Src Kinase Kd 6.25 CHEMBL
Fibroblast growth factor receptor 3 Kinase Kd 5.57 CHEMBL
Serine/threonine-protein kinase 35 Kinase Kd 6.21 CHEMBL
Insulin receptor Kinase AGONIST Kd 6.47 CHEMBL
SRSF protein kinase 1 Kinase Kd 5.74 CHEMBL
Dual specificity tyrosine-phosphorylation-regulated kinase 2 Kinase Kd 5.40 CHEMBL
Serine/threonine-protein kinase RIO3 Kinase Kd 5.40 CHEMBL
Dual specificity mitogen-activated protein kinase kinase 3 Kinase Kd 5.48 CHEMBL
Receptor-interacting serine/threonine-protein kinase 2 Kinase Kd 6.05 CHEMBL
Ephrin type-B receptor 4 Kinase Kd 6.24 CHEMBL
Tyrosine-protein kinase JAK2 Kinase Kd 6.54 CHEMBL
Serine/threonine-protein kinase NIM1 Kinase Kd 5.34 CHEMBL
Serine/threonine-protein kinase SBK1 Kinase Kd 5.89 CHEMBL
Mitogen-activated protein kinase kinase kinase 15 Kinase Kd 5.55 CHEMBL
Aurora kinase A Kinase Kd 6.59 CHEMBL
Tyrosine-protein kinase JAK1 Kinase Kd 6.48 CHEMBL
Tyrosine-protein kinase ITK/TSK Kinase Kd 5.70 CHEMBL
Tyrosine-protein kinase SYK Kinase Kd 5.60 CHEMBL
Interferon-induced, double-stranded RNA-activated protein kinase Kinase Kd 5.96 CHEMBL
Tyrosine-protein kinase BTK Kinase Kd 5.11 CHEMBL
Cyclin-dependent kinase 11B Kinase Kd 6.12 CHEMBL
Serine/threonine-protein kinase D1 Kinase Kd 6 CHEMBL
Mitogen-activated protein kinase kinase kinase 13 Kinase Kd 6.64 CHEMBL
Serine/threonine-protein kinase TBK1 Kinase Kd 6.16 CHEMBL
Ephrin type-A receptor 1 Kinase Kd 6.85 CHEMBL
Serine/threonine-protein kinase Nek7 Kinase Kd 5.24 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 1 Kinase Kd 7.41 CHEMBL
AarF domain-containing protein kinase 4 Kinase Kd 5.96 CHEMBL
Tyrosine-protein kinase Fgr Kinase Kd 6.17 CHEMBL
Serine/threonine-protein kinase D3 Kinase Kd 6.29 CHEMBL
Mitogen-activated protein kinase kinase kinase 7 Kinase Kd 5.74 CHEMBL
Tyrosine-protein kinase FRK Kinase Kd 5.54 CHEMBL
Ephrin type-A receptor 8 Kinase Kd 6.55 CHEMBL
Ephrin type-A receptor 2 Kinase Kd 7 CHEMBL
Ephrin type-A receptor 3 Kinase Kd 6.15 CHEMBL
Serine/threonine-protein kinase 10 Kinase Kd 7.36 CHEMBL
Tyrosine-protein kinase Fer Kinase Kd 6.57 CHEMBL
Serine/threonine-protein kinase PLK4 Kinase Kd 7.22 CHEMBL
AP2-associated protein kinase 1 Kinase Kd 5.64 CHEMBL
Tyrosine-protein kinase JAK3 Kinase Kd 6.70 CHEMBL
Tyrosine-protein kinase Yes Kinase Kd 6.11 CHEMBL
Serine/threonine-protein kinase TAO1 Kinase Kd 5.92 CHEMBL
Serine/threonine-protein kinase TNNI3K Kinase Kd 6.96 CHEMBL
Aurora kinase C Kinase Kd 5.37 CHEMBL
High affinity nerve growth factor receptor Kinase Kd 7.02 CHEMBL
Rho-associated protein kinase 1 Kinase Kd 5.43 CHEMBL
Ankyrin repeat and protein kinase domain-containing protein 1 Kinase Kd 6.11 CHEMBL
Homeodomain-interacting protein kinase 4 Kinase Kd 5.44 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 5 Kinase Kd 7.10 CHEMBL
Serine/threonine-protein kinase DCLK2 Kinase Kd 6.43 CHEMBL
Misshapen-like kinase 1 Kinase Kd 5.36 CHEMBL
Interleukin-1 receptor-associated kinase 4 Kinase Kd 5.44 CHEMBL
Insulin receptor-related protein Kinase Kd 6.22 CHEMBL
Mast/stem cell growth factor receptor Kit Kinase Kd 6.10 CHEMBL
BMP-2-inducible protein kinase Kinase Kd 6.13 CHEMBL
Insulin-like growth factor 1 receptor Kinase Kd 6.11 CHEMBL
Ephrin type-A receptor 6 Kinase Kd 7.19 CHEMBL
Calcium/calmodulin-dependent protein kinase kinase 2 Kinase Kd 5.82 CHEMBL
Aurora kinase B Kinase Kd 7.12 CHEMBL
STE20-like serine/threonine-protein kinase Kinase Kd 7.74 CHEMBL
Bone morphogenetic protein receptor type-1B Kinase Kd 6.64 CHEMBL
Macrophage-stimulating protein receptor Kinase Kd 7.60 CHEMBL
Non-receptor tyrosine-protein kinase TYK2 Kinase Kd 6.68 CHEMBL
Interleukin-1 receptor-associated kinase 1 Kinase Kd 7.31 CHEMBL
Serine/threonine-protein kinase 4 Kinase Kd 6.24 CHEMBL
Ephrin type-A receptor 7 Kinase Kd 6.33 CHEMBL
Serine/threonine-protein kinase 3 Kinase Kd 6 CHEMBL
Inhibitor of nuclear factor kappa-B kinase subunit beta Kinase Kd 5.26 CHEMBL
Serine/threonine-protein kinase Nek9 Kinase Kd 6.10 CHEMBL
Serine/threonine-protein kinase TAO2 Kinase Kd 6.05 CHEMBL
Tyrosine-protein kinase Lyn Kinase Kd 6.03 CHEMBL
5'-AMP-activated protein kinase catalytic subunit alpha-1 Kinase Kd 5.62 CHEMBL
Cytoplasmic tyrosine-protein kinase BMX Kinase Kd 5.44 CHEMBL
Ephrin type-A receptor 5 Kinase Kd 6 CHEMBL
LIM domain kinase 1 Kinase Kd 6.08 CHEMBL
NPM/ALK (Nucleophosmin/ALK tyrosine kinase receptor) Kinase IC50 7.29 CHEMBL
Serine/threonine-protein kinase ULK2 Kinase Kd 5.80 CHEMBL
Ephrin type-A receptor 4 Kinase Kd 6.44 CHEMBL
Ephrin type-B receptor 1 Kinase Kd 6.92 CHEMBL
Activated CDC42 kinase 1 Kinase Kd 6.12 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 3 Kinase Kd 7.12 CHEMBL
Dual specificity testis-specific protein kinase 1 Kinase Kd 6.42 CHEMBL
Focal adhesion kinase 1 Kinase Kd 6.51 CHEMBL
NT-3 growth factor receptor Kinase Kd 7.09 CHEMBL
Tyrosine-protein kinase ZAP-70 Kinase Kd 5.38 CHEMBL
Activin receptor type-1 Kinase Kd 6.36 CHEMBL
Interleukin-1 receptor-associated kinase 3 Kinase Kd 7.51 CHEMBL
G protein-coupled receptor kinase 4 Kinase Kd 5.38 CHEMBL
Mitogen-activated protein kinase kinase kinase 2 Kinase Kd 7.14 CHEMBL
Serine/threonine-protein kinase ULK3 Kinase Kd 5.17 CHEMBL
Abelson tyrosine-protein kinase 2 Kinase Kd 6.34 CHEMBL
Serine/threonine-protein kinase 26 Kinase Kd 5.55 CHEMBL
Protein-tyrosine kinase 2-beta Kinase Kd 6.72 CHEMBL
Tyrosine-protein kinase Blk Kinase Kd 6.96 CHEMBL
Angiopoietin-1 receptor Kinase Kd 6.57 CHEMBL
Inhibitor of nuclear factor kappa-B kinase subunit epsilon Kinase Kd 6.15 CHEMBL
Peripheral plasma membrane protein CASK Kinase Kd 6.85 CHEMBL
Dual serine/threonine and tyrosine protein kinase Kinase Kd 6.35 CHEMBL
Proto-oncogene tyrosine-protein kinase ROS Kinase Kd 8.39 CHEMBL
Ephrin type-B receptor 6 Kinase Kd 8.22 CHEMBL
Serine/threonine-protein kinase SIK2 Kinase Kd 6.70 CHEMBL
Serine/threonine-protein kinase TAO3 Kinase Kd 6.31 CHEMBL
Mitogen-activated protein kinase kinase kinase 1 Kinase Kd 5.96 CHEMBL
Cyclin-dependent kinase 7 Kinase Kd 6.48 CHEMBL
Rho-associated protein kinase 2 Kinase Kd 5.48 CHEMBL
Tyrosine-protein kinase Fyn Kinase Kd 5.89 CHEMBL
Macrophage colony-stimulating factor 1 receptor Kinase Kd 6.68 CHEMBL
Uncharacterized serine/threonine-protein kinase SBK3 Kinase Kd 6.62 CHEMBL
Activin receptor type-1B Kinase Kd 6.07 CHEMBL
Tyrosine-protein kinase receptor Tie-1 Kinase Kd 6.96 CHEMBL
TGF-beta receptor type-1 Kinase Kd 6 CHEMBL
Proto-oncogene tyrosine-protein kinase receptor Ret Kinase Kd 5.89 CHEMBL
Myotonin-protein kinase Kinase Kd 5.85 CHEMBL
Epithelial discoidin domain-containing receptor 1 Kinase Kd 6.29 CHEMBL
Tyrosine-protein kinase receptor TYRO3 Kinase Kd 6.10 CHEMBL
Tyrosine-protein kinase Fes/Fps Kinase Kd 6.35 CHEMBL
Tyrosine-protein kinase Lck Kinase Kd 7.52 CHEMBL
Leukocyte tyrosine kinase receptor Kinase Kd 7.92 CHEMBL
Mitogen-activated protein kinase kinase kinase 19 Kinase Kd 6.01 CHEMBL
Tyrosine-protein kinase receptor UFO Kinase Kd 8.11 CHEMBL
BDNF/NT-3 growth factors receptor Kinase Kd 7.43 CHEMBL
NUAK family SNF1-like kinase 2 Kinase Kd 6.92 CHEMBL
SRSF protein kinase 3 Kinase Kd 5.09 CHEMBL
Tyrosine-protein kinase TXK Kinase Kd 6.07 CHEMBL
LIM domain kinase 2 Kinase Kd 6.16 CHEMBL
Mitogen-activated protein kinase kinase kinase 12 Kinase Kd 6.77 CHEMBL
Receptor-interacting serine/threonine-protein kinase 1 Kinase Kd 5.80 CHEMBL
Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha Kinase Kd 5.49 CHEMBL
Mitogen-activated protein kinase kinase kinase 3 Kinase Kd 6.96 CHEMBL
Cyclin-dependent kinase 11A Kinase Kd 6.38 CHEMBL
Serine/threonine-protein kinase RIO1 Kinase Kd 5.21 CHEMBL
Ribosomal protein S6 kinase beta-1 Kinase Kd 6.19 CHEMBL
Serine/threonine-protein kinase ULK1 Kinase Kd 6 CHEMBL
Receptor-interacting serine/threonine-protein kinase 4 Kinase Kd 5.68 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 2 Kinase Kd 7.10 CHEMBL
Tyrosine-protein kinase Mer Kinase Kd 8.44 CHEMBL
Mitogen-activated protein kinase 7 Kinase Kd 6.29 CHEMBL
Receptor-type tyrosine-protein kinase FLT3 Kinase Kd 6.68 CHEMBL
Non-receptor tyrosine-protein kinase TNK1 Kinase Kd 6.49 CHEMBL
Cyclin-dependent kinase-like 2 Kinase Kd 5.68 CHEMBL
Angiopoietin-1 receptor Kinase IC50 6.35 CHEMBL
Tyrosine-protein kinase ABL1 Kinase IC50 5.94 CHEMBL
Macrophage-stimulating protein receptor Kinase IC50 7.10 CHEMBL

External reference:

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IDSource
CHEBI:64310 CHEBI
4903 IUPHAR_LIGAND_ID
4030983 VUID
N0000183253 NUI
C2974289 UMLSCUI
D09731 KEGG_DRUG
53AH36668S UNII
9301 INN_ID
1148495 RXNORM
013917 NDDF
28080 MMSL
d07800 MMSL
4030983 VANDF
N0000183253 NDFRT
703637000 SNOMEDCT_US
703638005 SNOMEDCT_US
CHEMBL601719 ChEMBL_ID
DB08865 DRUGBANK_ID
C551994 MESH_SUPPLEMENTAL_RECORD_UI
11626560 PUBCHEM_CID
VGH PDB_CHEM_ID

Pharmaceutical products:

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ProductCategoryIngredientsNDCFormQuantityRoute MarketingLabel
Xalkori HUMAN PRESCRIPTION DRUG LABEL 1 0069-8140 CAPSULE 250 mg ORAL NDA 19 sections
Xalkori HUMAN PRESCRIPTION DRUG LABEL 1 0069-8141 CAPSULE 200 mg ORAL NDA 19 sections