phl_425_tyrosine_kinase_inhibitors

Download Report

Transcript phl_425_tyrosine_kinase_inhibitors

Tyrosine Kinase Inhibitors
PHL 425
Dr. Mohamed M. Sayed-AShmed
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.
Tyrosine Kinases
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 crossphosphorylation 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.
MABs and TKIs
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.
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.
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.
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.
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.
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.
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.
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 %.
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.
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.
Clinically Used Tyrosine Kinase Inhibitors
* Imatinib
* Sunitinib
* Dasatinib
* Nilotinib
* Gefitinib
* Erlotinib
* Sorafenib