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Tyrosine Kinase Inhibitors PHL 417

Tyrosine Kinase Inhibitors PHL 417. Tyrosine Kinases. There are 2 major classes of tyrosine kinases.

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Tyrosine Kinase Inhibitors PHL 417

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  1. Tyrosine Kinase InhibitorsPHL 417

  2. Tyrosine Kinases There are 2 major classes of tyrosine kinases. 1- Receptor tyrosine kinases (RTKs) which are embedded in the cell membrane with an extracellular ligand-binding domain and an intracellular kinase domain that signals to the interior of the cell. 2- Nonreceptor tyrosine kinases (NRTKs) are located within the cell. By their location, tyrosine kinases can mediate transduction of both extracellular and intracellular signals. Because of their critical role in normal cellular communication and maintenance of homeostasis, tyrosine kinase activity is tightly regulated. Tyrosine kinases are normally quiescent until activated by extracellular stimuli or ligands, such as growth factors (eg, VEGF, PDGF]) or intracellular stimuli (such as oxidant stress, activating NRTKs). An exquisite balance between activity of tyrosine kinases and of tyrosine phosphatases, which mediate dephosphorylation of tyrosine residues and therefore act in opposition to kinases, controls the timing and duration of cell signaling. RTKs phosphorylate target proteins by transferring gamma phosphate from ATP molecules to a hydroxyl group on tyrosine residues in protein substrates. Thus, they regulate cell cycle, proliferation, differentiation, migration, metabolism and survival.

  3. Tyrosine Kinases

  4. Mechanism of carcinogenesis of BCR-ABI in CML

  5. Targeting TKs Two classes of targeted tyrosine kinase therapeutics have been developed: 1- mAbs are designed to bind to the extracellular portion of RTKs, thereby inhibiting tyrosine kinase activation (Figure 2). The binding of mAbs to the extracellular domain of the RTKs can block ligand binding to the receptor, inhibit subsequent dimerization and activation of the tyrosine kinase domain, and/or induce downregulation of expression of the receptor. An example of a mAb that binds to receptors is trastuzumab (Herceptin; Genentech), which binds to the HER2 receptor . 2- Small molecule TKIs have been designed to target both classes of tyrosine kinases: RTKs and NRTKs. Inhibitors of RTKs block activity of the intracellular kinase domain. Normally, ligand binding to a RTK initiates dimerization and crossphosphorylation of one kinase domain by the other, thereby activating the kinase (Figure 2). The activated kinase dimer then phosphorylates downstream substrates in a signaling cascade that ultimately results in changes such as altered gene expression and cell proliferation. TKIs can directly inhibit the cross-phosphorylation of the kinase domains and also inhibit phosphorylation of downstream substrates, thereby terminating the signaling cascade. TKIs that block signaling by NRTKs (eg, Abl) target intracellular kinases and work in a fashion similar to those that target RTKs.

  6. MABs and TKIs

  7. Types of TKIs TKIs can block substrate phosphorylation in 3 ways. Substrate phosphorylation is dependent on the binding of both ATP and the substrate to an activated kinase. Type I inhibitors: (eg, sunitinib) compete with ATP for binding to the ATP pocket of a fully activated kinase and are by far the dominant type in use today. However, they generally lack selectivity because There are more than 500 kinases that share similar structure of ATP-pocket. Type II inhibitors: (eg, imatinib and nilotinib) bind 2 different regions on the kinase: the ATP pocket and an adjacent region that is accessible only when the kinase is inactive. Type II inhibitors thus bind and lock kinases in an inactive state. Type II TKIs generally are more potent and more selective than type I although they inhibit 3 kinases. Type III inhibitors: (eg, ERK ( extracellular signal-regulated kinase) selective blocker (U0126) bind to sites Other than ATP pocket, such as the substrate recognition region (blocking binding of substrate to kinase). Consequently, type III inhibitors promise to be the most selective. Despite their potential for greater selectivity, however, type III inhibitors represent a small minority of TKIs in development because they are more difficult to design and not as predictably effective. Overall, TKIs are less selective than mAbs and inhibit several kinases, some known and others not.

  8. TYROSINE KINASE INHIBITORS IMATINIB (Gleevec) • Imatinib mesylate is an antineoplastic agent that inhibits the Bcr-Abl fusion protein tyrosine kinase, an abnormal enzyme produced by chronic myeloid leukemia cells that harbor the Philadelphia chromosome. • Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF)/c-kit; the SCF/c-kit receptor tyrosine kinase is activated in gastrointestinal stromal tumor (GIST). This agent inhibits proliferation and induces apoptosis in cells that overexpress these oncoproteins.

  9. IMATINIB (Gleevec) The ordinary BCR and ABL genes code for separate proteins that have little or no Kinase activity. The fusion gene codes for super active tyrosine kinase, causing CML. Imatinib inhibits this fusion and targets CML.

  10. GEFITINIB (Iressa) • Gefitinib inhibits the catalytic activity of numerous tyrosine kinases including the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase-dependent tumor growth. • Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction. • Gefitinib may also induce cell cycle arrest and inhibit angiogenesis.

  11. SUNITINIB (Sutent) The orally bioavailable malate salt of an indolinone-based tyrosine kinase inhibitor with potential antineoplastic activity. Sunitinib blocks the tyrosine kinase activities of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor beta (PDGFRb), and c-kit, thereby inhibiting angiogenesis and cell proliferation.

  12. SUNITINIB Indication: Sunitinib is FDA approved in 2006 as TKI in the treatment of Metastatic Renal Cell Carcinoma (MRCC) , Gastrointestinal Stromal Tumour and Pancreatic Neuroendocrine Tumors (PNET) . For both RCC and GIST, Sunitinib is taken orally at 50 mg once daily for 4 weeks on, followed by 2 weeks off (schedule 4/2). The recommended dose for PNET is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. SUTENT may be taken with or without food. According to individual patient’s safety and tolerability, the dose may be increased or decreased by 12.5 mg. Sunitinib is available in the form of 12.5, 25, and 50 mg capsules.

  13. SUNITINIB Pharmacokinetics: Following oral administration, Sunitinib reaches maximum plasma concentration (Cmax) after 6 to 12 hours. Food has no effect on the bioavailability. CYP3A4 is the primary metabolizing enzyme for both drug and metabolite. Concomitant administration of sunitinib with strong CYP3A4 inducer such as Rifampicin, resulted in 23 % decrease in Cmax, thus the dose may be increase to 87.5 mg. Inhibitors of CYP3A4 such as Ketoconazole increased Cmax by 49 %, therefore, dose reduction to a minimum of 37.5 mg is considered.

  14. SUNITINIB Pharmacokinetics: Have high protein binding 95 % and 90 %, respectively. Vd is approximately 2230 L. Sunitinib Half-life is 40-60 hours. The main metabolite half-life is longer (80-110 hours). Sunitinib is mainly eliminated in feces (61 %) and renal excretion represents 16 %.

  15. SUNITINIB Adverse Effects: The most common adverse reactions are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding.

  16. SUNITINIB Cardiotoxicity Hypertension Decrease in left ventricular ejection fraction (LVEF), which is the fraction of blood pumped oout of LV witheach heart beat. QT interval prolongation (torsade de point). Congestive Heart Failure. Mecahnism of Sunitinib-induced cardiotoxicity: 1- Inhibition of Ribosoma S6 Kinase 2- Inhibition of AMP-activated protein kinase. 3- Increased expression of cardiac hypertrophic genes.

  17. Clinically Used Tyrosine Kinase Inhibitors * Imatinib * Sunitinib * Dasatinib * Nilotinib * Gefitinib * Erlotinib * Sorafenib

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