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TYROSINE KINASEINHIBITORSAhmad Aljifri1
Outline• Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy•...
Protein Kinase• Is kinase enzyme that modifies other proteins by chemicallyadding phosphate groups to them (phosphorylatio...
Categories of Protein Kinases1. Kinases that specifically phosphorylatetyrosine residues.2. Kinases that phosphorylate ser...
Tyrosine Kinase• Is an enzyme that can transfer a phosphate groupfrom ATP to a protein in a cell.• It functions as an "on"...
Tyrosine Kinase Types1. Receptor tyrosine kinaseseg: EGFR, PDGFR, FGFR2. Non-receptor tyrosine kinaseseg: SRC, ABL, FAK an...
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8
9
Oncogenic Activation of Receptor Tyrosine Kinases• Normally the level of cellular tyrosine kinasephosphorylation is tightl...
Targeted Therapy• is a type of medication that blocks the growth of cancercells by interfering with specific targeted mole...
12
Tyrosine Kinase Inhibitor1. BCR-ABL Tyrosine Kinase Inhibitorseg: Imatinib, Dasatinib, Nilotinib.2. Epidermal Growth Facto...
Imatinib (Gleevec)• MOA:Inhibits Bcr-Abl tyrosine kinase, the constitutive abnormalgene product of the Philadelphia chromo...
Imatinib (Gleevec)Toxicity:• Cardiovascular: Edema/fluid retention (11% to 86%)• Central nervous system: Fatigue (29% to 7...
Dasatinib• MOA:BCR-ABL tyrosine kinase inhibitor; targets most imatinib-resistant BCR-ABL mutations.• Indication:Ph+ CMLPh...
DasatinibToxicity:• Cardiovascular: Fluid retention (21% to 35%)• Central nervous system: Headache (12% to 33%), fatigue (...
Gefitinib• MOA:Gefitinib is a tyrosine kinase inhibitor (TKI) which inhibitsnumerous tyrosine kinases associated with tran...
GefitinibToxicity• Dermatologic: Rash (43% to 54%), acne (25% to 33%), dryskin (13% to 26%), paronychia (14%)• Gastrointes...
Lapatinib• MOA:Tyrosine kinase (dual kinase) inhibitor; inhibits EGFR (ErbB1) andHER2 (ErbB2). Combination therapy with la...
LapatinibToxicity• Central nervous system: Fatigue (10% to 20%), headache (≤14%)• Dermatologic: (hand-and-foot syndrome) (...
Sorafinib• MOA:Multikinase inhibitor; inhibits tumor growth and angiogenesis byinhibiting intracellular Raf kinases, and c...
SorafinibToxicity• Cardiovascular: Hypertension (9% to 17%)• Central nervous system: Fatigue (37% to 46%),• Dermatologic: ...
Drug InteractionsStrong CYP3A4 Inhibitors:ketoconazole, itraconazole, voriconazole, posiconazoleclarithromycin, telithromy...
Reference• Managing Side Effects of TKI Therapy to Optimize Adherence in Patients withChronic Myeloid Leukemia http://goo....
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Tyrosine kinase inhibitors

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TKI introduction and some of its drugs and side effects
many thanks to Vijay Yerroju
most of the info is taken from his presentation on TKI

Published in: Health & Medicine, Technology
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Transcript of "Tyrosine kinase inhibitors"

  1. 1. TYROSINE KINASEINHIBITORSAhmad Aljifri1
  2. 2. Outline• Introduction-Protein Kinase-Categories of Protein Kinases-Tyrosine Kinase-Tyrosine Kinase Types-Targeted Therapy• Tyrosine Kinase Inhibitor2
  3. 3. Protein Kinase• Is kinase enzyme that modifies other proteins by chemicallyadding phosphate groups to them (phosphorylation)• The phosphate is often taken from ATP• Phosphorylation of proteins by kinases is animportant mechanism in communicatingsignals within a cell (signal transduction)and regulating cellular activity, such ascell division.3
  4. 4. Categories of Protein Kinases1. Kinases that specifically phosphorylatetyrosine residues.2. Kinases that phosphorylate serine andthreonine residues.4
  5. 5. Tyrosine Kinase• Is an enzyme that can transfer a phosphate groupfrom ATP to a protein in a cell.• It functions as an "on" or "off" switchin many cellular functions.• The phosphate group is attached to theamino acid tyrosine on the protein.5
  6. 6. Tyrosine Kinase Types1. Receptor tyrosine kinaseseg: EGFR, PDGFR, FGFR2. Non-receptor tyrosine kinaseseg: SRC, ABL, FAK and Janus kinase6
  7. 7. 7
  8. 8. 8
  9. 9. 9
  10. 10. Oncogenic Activation of Receptor Tyrosine Kinases• Normally the level of cellular tyrosine kinasephosphorylation is tightly controlled by theantagonizing effect of tyrosine kinaseand tyrosine phosphatases.• Some Common mechanismsof oncogenic activation:1. Activation by mutation2. BCR-ABL and human leukemia10
  11. 11. Targeted Therapy• is a type of medication that blocks the growth of cancercells by interfering with specific targeted molecules neededfor carcinogenesis and tumor growth.• rather than by simply interfering with all rapidly dividingcells (e.g. with traditional chemotherapy).11
  12. 12. 12
  13. 13. Tyrosine Kinase Inhibitor1. BCR-ABL Tyrosine Kinase Inhibitorseg: Imatinib, Dasatinib, Nilotinib.2. Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitorseg: Gefitinib, Lapatinib.3. Vascular Endothelial GrowthFactor Tyrosine Kinase Inhibitorseg: Semaxinib, Vandalinib,Sunitinib, Sorafenib.13
  14. 14. Imatinib (Gleevec)• MOA:Inhibits Bcr-Abl tyrosine kinase, the constitutive abnormalgene product of the Philadelphia chromosome in chronicmyeloid leukemia (CML).• Indication:Ph+ CMLPh+ ALLGISTwebsite:http://www.gleevec.com/index.jsp14
  15. 15. Imatinib (Gleevec)Toxicity:• Cardiovascular: Edema/fluid retention (11% to 86%)• Central nervous system: Fatigue (29% to 75%), pain (≤47%), fever (6% to 41%),headache (8% to 37%), dizziness (5% to 19%)• Dermatologic: Rash (9% to 50%), dermatitis (GIST ≤39%), alopecia (GIST 10% to15%)• Endocrine & metabolic: LDH increased (GIST ≤60%),• Gastrointestinal: Nausea (42% to 73%; Ph+ ALL), diarrhea (25% to 59%; Ph+ALL), vomiting (11% to 58%), abdominal pain (3% to 57%), anorexia (≤36%),weight gain (5% to 32%),• Hematologic: Anemia (25% to 80%), leukopenia (GIST 5% to 47%), hemorrhage(3% to 53%), neutropenia (12% to 16%)• Hepatic: Transaminases and/or bilirubin increased (57%)• Neuromuscular & skeletal: Muscle cramps (16% to 62%)• Ocular: Periorbital edema (29% to ≤74%)• Renal: Serum creatinine increased (≤44%)• Respiratory: cough (11% to 27%), upper respiratory tract infection (3% to 21%)• Miscellaneous: Infection (Ph+ ALL 53%; GIST ≤28%)15
  16. 16. Dasatinib• MOA:BCR-ABL tyrosine kinase inhibitor; targets most imatinib-resistant BCR-ABL mutations.• Indication:Ph+ CMLPh+ ALLwebsite:https://www.sprycel.com/index.aspx16
  17. 17. DasatinibToxicity:• Cardiovascular: Fluid retention (21% to 35%)• Central nervous system: Headache (12% to 33%), fatigue (8% to24%), fever (5% to 18%)• Dermatologic: Rash (11% to 21)• Endocrine & metabolic: Hypophosphatemia (5% to 18%)• Gastrointestinal: Diarrhea (18% to 31%), nausea (9% to 24%),vomiting (5% to 16%), abdominal pain (3% to 12%)• Hematologic: Thrombocytopenia (19% to 85%), neutropenia (22%to 79%), anemia (11% to 74%), neutropenic fever (1% to 12%)• Neuromuscular & skeletal: Musculoskeletal pain (≤19%)• Respiratory: Pleural effusion (12% to 24%)• Miscellaneous: Infection (9% to 12%)17
  18. 18. Gefitinib• MOA:Gefitinib is a tyrosine kinase inhibitor (TKI) which inhibitsnumerous tyrosine kinases associated with transmembrane cellsurface receptors found on both normal and cancer cells, includingthe tyrosine kinase associated with the epidermal growth factorreceptor, EGFR.• Indications:Non-small Cell Lung Cancer (NSCLC)Monotherapy for continued treatment of locally advanced ormetastatic NSCLC after failure of both platinum-based andDocetaxel regimens• websitehttp://www.iressa.com18
  19. 19. GefitinibToxicity• Dermatologic: Rash (43% to 54%), acne (25% to 33%), dryskin (13% to 26%), paronychia (14%)• Gastrointestinal: Diarrhea (48% to 67%), nausea (13% to18%), vomiting (9% to 12%)19
  20. 20. Lapatinib• MOA:Tyrosine kinase (dual kinase) inhibitor; inhibits EGFR (ErbB1) andHER2 (ErbB2). Combination therapy with lapatinib and endocrinetherapy may overcome endocrine resistance occurring in HER2+and hormone receptor positive disease.• Indications:Metastatic Breast Cancer in combination with Capecitabine inpatients whose tumors overexpress HER2 and who have receivedprior therapy including an Anthracycline, a Taxane, andTrastuzumab.websitehttp://www.tykerb.com/20
  21. 21. LapatinibToxicity• Central nervous system: Fatigue (10% to 20%), headache (≤14%)• Dermatologic: (hand-and-foot syndrome) (with capecitabine: 53%),rash (28% to 44%), alopecia (≤13%)• Gastrointestinal: Diarrhea (64% to 65%), nausea (31% to 44%),vomiting (17% to 26%),• Hematologic: Anemia (with capecitabine: 56%), neutropenia (withcapecitabine: 22%)• Hepatic: total bilirubin increased (22% to 45%)• Neuromuscular & skeletal: weakness (≤12%), back pain (≤11%)• Respiratory:Dyspnea (≤12%)21
  22. 22. Sorafinib• MOA:Multikinase inhibitor; inhibits tumor growth and angiogenesis byinhibiting intracellular Raf kinases, and cell surface kinase receptors(VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta, cKIT, FLT-3, andRET).• Indications:Treatment of advanced renal cell cancer (RCC); treatment ofunresectable hepatocellular cancer (HCC)websitehttp://www.nexavar-us.com/scripts/pages/en/patient/index.php22
  23. 23. SorafinibToxicity• Cardiovascular: Hypertension (9% to 17%)• Central nervous system: Fatigue (37% to 46%),• Dermatologic: Rash (19% to 40%), hand-foot syndrome (21% to30%), alopecia (14% to 27%)• Endocrine & metabolic: Hypoalbuminemia (≤59%),• Gastrointestinal: Diarrhea (43% to 55%), weight loss (10% to30%),, nausea (23% to 24%), vomiting (15% to 16%), constipation(14% to 15%)• Hematologic: Lymphopenia (23% to 47%),• Hepatic: Liver dysfunction (≤11%)• Neuromuscular & skeletal: Muscle pain, weakness• Respiratory: Dyspnea (≤14%), cough (≤13%)23
  24. 24. Drug InteractionsStrong CYP3A4 Inhibitors:ketoconazole, itraconazole, voriconazole, posiconazoleclarithromycin, telithromycinatazanavir, indinavir, nelfinavir, ritonavir, saquinavir,nefazodoneModerate CYP3A4 Inhibitors:fluconazole, erythromycin, aprepitant, grapefruit juice,verapamil, cimetidine24
  25. 25. Reference• Managing Side Effects of TKI Therapy to Optimize Adherence in Patients withChronic Myeloid Leukemia http://goo.gl/CE49F• http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2005/030805• http://www.Lexicopm.com• https://www.youtube.com/watch?v=zE4BkAw_lL425
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