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Aya Abou Issa

on 13 May 2014

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Tyrosine kinases
Cyclin-dependent kinase inhibitor
advances in genetic and
molecular biology
Histidine kinase inhibitor

Cytoplasmic ( non-receptor)
Non-receptor tyrosine kinase inhibitors :
• ABL tyrosine kinase inhibitors
• SCR tyrosine kinase inhibitors
• Tec tyrosine kinase (Bruton's kinase inhibitor )
•Transmembrane receptor-linked kinases
Brief introduction
...is always useful
Targeted cancer therapies
1. Signal transduction inhibitors
What is cancer
Dysfunction in normal cell
Loss of apoptosis mechanism or over-production of enzymes or receptors
Immortal uncontrolled divided cells
( localized )
( metastasis )

(forming of new blood vessels )
Cancer cell
Cell growth ( metastasis )
Cancer cell
No cell growth ( 1-2 mm )
Anti-VEGF receptor
Bevacizimab ( Avastin®)
huminized monoclonal Ab , colorectal ,lung , renal cancer
Sunitinib ( Sutent®)
kidney cancer and
neuroendocrine tumors
Pazopanib ( Votrient )
for kidney cancer
Sorafenib ( Nexavar )
hepatocellular carcinoma and
kidney cancer , FDA 2009
Cancer treatment
The choice of therapy depends on the
and the
of the tumor and the
of the disease as well as the general state of the patient

1- surgery
2- immunotherapy
3- radiotherapy
4- chemotherapy
Hormones and
Cytotoxic agents
Targeted cancer
Alkylating agents

Cytotoxic antibiotics
Plant products
Cytotoxic agents

Toxic for healthy cells especially rapidly dividing cells as liver , bone marrow , gastrointestinal mucosa .
Targeted cancer therapy
What is meant by oncogenes
Gene that has the potential to cause cancer. They are often mutated or over expressed.
Activated oncogenes cause normal cells escape from apoptosis survive and proliferate instead (
Most oncogenes require an activation step
( proto-oncogenes oncogenes through mutation or ampification or translocation )
molecular targets
more selective
less toxic
2. Monoclonal antibody (MAB) therapy
extracellular signal
cell-cell communication
cell’s response to
ordered sequences of biochemical reactions
(carried out by enzymes activated by second messengers)
signal transduction pathway
in signaling pathway and suitable targets
(growth factor , signal protein kinase)
anticancer agents
Protein kinases
enzymes that
specific amino acid in protein substrates.
Phosphorylation is a
process (proteins can be dephosphorylated by ezymes called
of gene in DNA cell growth and division.
Protein kinases
(within cytoplasm of cell)
(transverse cell membrane)
Protein kinase receptors
extracellular binding site for chemical messenger
intracellular kinase active site
(variety of growth factors)
activated when chemical messenger binds to receptor binding site
active enzyme binds to substrate and ATP
phosphorylation of substrate
cascade of signals
cell growth(division)
In cancer cells
excess kinase receptors and abnormal protein kinase
continuous cell division
protein kinase inhibitors would be useful as
selective anti cancer agents
Kinase inhibitors for treatment of cancer
Tyrosine kinase inhibitors
Cyclin dependent kinase inhibitors
Histidine kinase inhibitors
1) First generation ABL tyrosine kinase inhibitor
imatinib mesylate ( gleevec , glivec )
phenylaminopyrimidin derivative
milestone in anticancer therapy
chronic myeloid leukemia ( CML )
50 %
90 % of patients.
In 2001 , imatinib was first line treatment for chronic myeloid leukemia (CML), it was also approved in 2002 for the treatment of metastatic malignant gastrointestinal tumors.
Mechanism of action
• The pathogenesis of CML involves a characteristic genetic abnormality:
fusion of the
Abelson tyrosine kinase
(abl) proto-oncogene in chromosome 9 with the
breakpoint cluster region
(bcr) gene
(now known as GTPase-activating protein(GAP) in chromosome 22.
resulted hybrid oncogene bcr-abl
[ termed the Philadelphia (Ph) chromosome ]
encode for excessive levels of Abl-bcr tyrosine kinase
excessive quantities of leukocytes
Fluorescence in situ hybridization using unique-sequence,

double-fusion DNA probes for bcr

in red and
c-abl gene regions
in green. The

abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells
is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD.
Mechanism of action (cont.)
• Imatinib is a
competitive selective
inhibitor for BCR-ABL tyrosine kinase , by binding to the ATP bindig site in the inactive
form of the enzyme leading to
of the enzyme activity , resulting in both
hematologic response
(ie, normal cell counts in the peripheral blood and normal bone marrow morphology), as well as
cytogenetic response
(ie, disappearance or reduction of the Philadelphia [Ph] chromosome).
• Selectivity
It shows specificity for BCR-ABL
also the receptor for
platelet-derived growth factor
, which its excessive levels contribute to the appearance of certain types of cancer
c-kit tyrosine kinases, which activated by stem cell factor
and implicated in certain types of
cancer .
The fact that it is not totally selective and inhibits various different kinases led to the concern that it would have serious side effects.
this is not the case
As normal cells are able to survive inhibition of these kinases , whereas the survival of CML cells relies crucially on Bcr – Abl .
Alkylation -> loss of activity
conformational blocker
unique selectivity
Aqueous solublity
• Drug resistance
Bcr-Abl dependant
Bcr-Abl Independent
BCR-ABL gene amblification
BCR-ABL gene mutation
i. T315I mutation
base pair substitution
(T)hreonine being substituted by (I)soleucine
creates steric hindrance to the binding of most TKIs
eliminates a critical oxygen molecule needed for hydrogen bonding between imatinib and the Abl kinase
common pathway to failure of both first and second line treatments
ii. P-loop mutation
the structure of Bcr-Abl contains two flexible loops, the ATP-binding P-loop and the activation loop
specific arrangements that stabilize the basal conformation
destabilize arrangement of the loops
kinase domain cannot assume the inactive conformation required for imatinib binding
ii. Drug efflux caused by
i. Drug import by organic cation transporter 1
Patients with low expression, activity or polymorphisms of OCT1
lower intracellular levels of imatinib
iii. Alternative signaling pathway activation
particularly the Src family kinases
mediate imatinib resistance by stabilizing the active conformation of Bcr-Abl
As a result , second generation was developed !
2) Second generation tyrosine kinase inhibitors
(inhibit Abl , Src and other kinases )
decreased resistance and intolerance than imatinib
nilotinib, dasatinib, bosutinib , and
Ponatinib (Iclusig)
• Some forms of CML, those that have the T315I mutation
Ponatinib was approved by the US FDA on December 14, 2012, as a second line treatment for patients with CML resistant to imatinib
• Mechanism of action
multi-targeted tyrosine-kinase inhibitor (ABL and T315I mutant ABL)
binding to the
ATP bindig site
in the inactive (non-phosphorylated) form of the enzyme leading to blocking of the enzyme activity
FDA temporarily suspended sales of the drug in the U.S. on 31 October 2013 because of “the risk of life-threatening
blood clots
and severe
narrowing of blood vessels
Black Box Warning !
3) Tec tyrosine kinases (Bruton's kinase inhibitor )
a key component of B-cell receptor (BCR) signalling
important regulator of B-cell activation proliferation and cell survival in various B cell malignancies , leukemia, and autoimmune diseases
Ibrutinib (Imbruvica )
In November 2013, the FDA granted approval of imbruvica to treat patients with mantle cell lymphoma.
In February 2014 , FDA expanded the approved use of Imbruvica (ibrutinib) for chronic lymphocytic leukemia (CLL) patients.
increase the progression-free survival rate to
• Mechanism of action
forms a covalent bond with a cysteine residue in the BTK active site
inhibition of BTK enzymatic activity
BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways
BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion
represent a change from general to molecular methods of cancer treatment
Growth factors
involved in the initialization and regulation of cell cycles
The type of growth factor determines its effects on the cell
There are three primary
1. Epidermal growth factors (EGF) help regulate cell growth and differentiation
2. Platelet-derived growth factor (PDGF) regulates cell growth & developpment
3. Vascular endothelial growth factors (VEGFR) are involved in the creation of blood vessels
The growth factors, and the kinases, act as though they are attached to an “on/off” switch
Tyrosine kinases as targets for anticancer agents
Site of targeting
Inhibiting the activity of tyrosine kinases by low molecular weight compounds capable of interfering with either ligand binding (in the case of receptor tyrosine kinases) or with protein substrate (in case of non receptor tyrosine kinase) has proved to be
Approaches to generate non-competitive or allosteric inhibitors have also failed
The ATP competitive inhibitors appear to be the target of choice
The ATP binding site
ATP binds within a deep cleft formed between the two lobes of the tyrosine kinase domain
Though the ATP binding site is highly conserved the architecture in the regions proximal to the ATP binding site does afford some key diversity for designing new drug and has potential application in drug discovery
Imatinib (brand name: Gleevac )
gefinitib (Iressa)
Serine/threonine-specific protein kinase
phosphorylates the OH group of serine or threonine (which have similar sidechains)
plays a role in the regulation of cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development
Serine/theronine inhibitors
BRaf inhibitors
are approved by FDA for treatment of late-stage melanoma
MEK inhibitor
Cobimetinib - Selumetinib - Trametinib
Histidine kinase
act as cellular receptors for signaling molecules in a way analogous to tyrosine kinase receptors (RTK)
are parts of a
signal transduction mechanisms
i,e. HK transfers a phosphate group from
to a histidine residue within the kinase
then to an
aspartate residue
on a 'receiver domain' on a different protein
that aspartyl phosphate residue is thus activated for signaling.
In terms of enzymology, a histidine kinase is an enzyme that catalyzes the chemical reaction
ATP + protein L-histidine ADP + protein N-phospho-L-histidine
Histidine kinase inhibitors
1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125)
Gifitinib (Iressa)
Approved by US F.D.A on May 5,2003
An anilinoquinazoline
locally advanced for
metastatic non-small cell lung cancer
after failure
of both platinum based and docetaxel chemotherapies
a selective chemotherapeutic agent
Adverse drug reactions (ADRs) are
for a potentially fatal disease
blocks Oxidation of para position
has similar size and lipophilicity of methyl group
alkoxy substituent at the 6-position
morpholine ring which is well known to enhance water solubility of gifitinib because of its basic Nitrogen atom
SAR (cont.)
Gifitinib mimics ATP and bind to ATP-binding region of the kinase active site
2 important hydrogen bonding interactions between the purine base of ATP and the protein backbone between amino acids Gln-767 and Met-769
one of these interactions involves the purine group acting as a
hydrogen bond donor
, while the other involves purine acting as
hydrogen bond acceptor
has 2 nitrogen atoms in the quinazoline ring which both ast as hydrogen bond acceptors
one of these interacts directly with Met-769
the other interacts with a bridgeing water molecule which interacts in turn with the hydroxyl group of thr-830
aniline ring occupies the normally vacant
hydrophobic pocket
opposite the ribose binding pocket
Mechanism of action
first selective
inhibitor of epidermal growth factor receptor's
tyrosine kinase domain
EGFR is overexpressed in the cells of certain types of human carcinomas (lung and breast cancers)
inappropriate activation of the
anti-apoptotic Ras
signalling cascade
cell proliferation
Mechanism of action (cont.)
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate
(ATP)-binding site
of the enzyme
Function of the EGFR tyrosine kinase in activating the anti-apoptotic Ras signal transduction cascade is
malignant cells are
Eman Harfoush
Eman Nasser
Aya Atef
Aya Abou Issa
Aya Mostafa
Braa Zakareya
Perihane Morsi
Basma Zidan

Aya Abou Issa
...also known as serine-threonine kinases
(CDIs, CKIs or CDKIs)
Growth Suppressor genes
• Regulate cell cycle , transcription , mRNA processing
Present in all known eukaryotes
Cyclin-dependent kinase inhibitor drugs
1. Flavopiridol (Alvocidib)
yet approved by the U.S. Food and Drug Administration (FDA)
S.E: diarrhea, nausea and vomiting, and cytokine release syndrome (fever, flushing tachycardia, nausea)
MEK inhibitors :
1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125)
eukaryotic elongation factor 2 Kinase Inhibitor
regulation of protein synthesis:
phosphorylates (eEF2)
inhibits itsfunction
eEf2 is an essential factor for protein synthesis
promotes the GTP-dependent translocation of the ribosome
This protein is completely inactivated by EF-2 kinase phosphorylation
HKI (cont.)
Inhibitors of prokaryotic histidine kinases might also inhibit the activity of eEF-2 kinase
Screening of a series of
histidine kinase inhibitors and the identification of an active lead compound,
inhibited eEF-2 kinase activity in
blocked the
of eEF-2 in intact cells
showed relative
over other protein kinases
Under standard kinase assay conditions, NH125 exhibits a
similar weak ability
to inhibit the phosphorylation of eEF2 by eEF-2K
• Without cyclin , CDK has little kinase activity (Low phosphorylation)
• CDKs Phosphorylate their Substrates On Serine & Threonines
Block kinase activity (During
CDKI , Competes for
ATP site
of the CDKs , anticancer agent
2. Aminothiazoles
3. Pyrimidines
4. Seliciclib
: Undergoing clinical trials (Potential anti-cancer drug)
 Mitogen-activated protein kinase enzyme inhibitor
 Types : MEK1 & MEK2
 Over active in some cancers
  Treat BRAF-mutated Melanoma
Trametinib ,cobimetinib,Selumitinib (for phase 2 {NSCLC} Non-small cell lung Cancer)
BRAF inhibitor
 It is a human gene that forms a protein called :B-Raf
 Also BRAF is called Proto-Oncogene
Dabrafenib ,Vemurafenib
Trametinib (MEK inhibitor) + Dabrafenib (RAF inhibitor ) are used as a combination for treating BRAF-mutated Melanoma.
Tyrosine kinase inhibitors (TKIs) are a class of chemotherapy medications that inhibit, or block, the enzyme tyrosine kinase.
TKIs are created out of modern genetics- the understanding of DNA, the cell cycle, and molecular signaling pathways
thus represent a change from
general to molecular
methods of cancer treatment
targeted treatment of specific cancers
the risk of damage to healthy cells & treatment success.
an eukaryotic elongation factor 2 Kinase Inhibitor
(will be discussed later)

essential for selectivity
Full transcript