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An introduction to kinases and kinase inhibitors

This is a draft working document that will be updated over time to include a larger range of kinases and the
techniques and molecules used to block their action in order to treat diseases.
Current version 01 – 22 December 2016
Protein kinases are complex enzymes that regulate cell function by catalysing the transfer of a phosphate group
from adenosine triphosphate (ATP) to a substrate (usually a protein) within a cell. This results in a
conformational change of the substrate that sets in motion a cascade of processes and signals that control the
cell cycle : cell division, cell growth, proliferation, cell death. The action of a kinase is catalytic in nature in
that it very significantly speeds up the phosphorylation reaction but is not consumed in the process.
In many of the cases involved in diseases, the action of the kinase may be subject to interaction by a third party
molecule called a ligand which attaches to Receptor Protein Kinases. These are trans-membrane protein
kinases with a ligand receptor pocket on the outer surface of the cell and a phosphate receiving receptor inside
the cell. For phosphorylation process to occur the receptor kinase must first be activated by the ligand locking
on to the extracellualr receptor which induces a conformational change inside the cell enabling the transfer of
the phosphate group to the protein. In this sense the ligand functions as an "on" or "off" switch for many
cellular functions.
Normal activation of these processes is necessary for a healthy cell cycle, whereas excessive activation or nonactivation may lead to dysfunction and disease. There are a very large number of diseases for which kinase
receptor dysfunction is implicated. These range from auto-immune diseases, to inflammatory diseases and
cancer.
To activate the cell cycle cascade, the ligand must physically
and chemically lock into the protein receptor and remain
long enough for the transfer of the phosphate group to the
receptor protein. This is a competitive process where a
ligand may fit the lock of several receptors to different
degrees (with or without enabling the transfer of the
phosphate group) and a given receptor may accept several
ligands, each having different degrees of activity.
Kinase inhibitors are molecules that block or interfere with
the phosphorylation process. This can be done in a number
of ways : by connecting to and modifying the physical shape
of the kinase thus interfering with the cell cycle process or
by binding to the receptor pocket and so blocking access by
an active ligand, etc.
There are 518 human protein kinases of which 478 belong
to a single superfamily whose catalytic domains are related
in sequence. These can be clustered into groups, families
and sub-families, of increasing sequence similarity and
biochemical function.
The kinase dendrogram shows the sequence similarity
between these catalytic domains: the distance along the branches between two kinases is proportional to the
divergence between their sequences. Seven major groups are labelled and coloured distinctly. For instance, the
tyrosine kinases form a distinct group, whose members phosphorylate proteins on tyrosine residues, whereas

enzymes in all other groups phosphorylate primarily serine and threonine residues. The relationships shown on
the tree can in some instances be used to predict protein substrates and biological function for many of the over
100 uncharacterised kinases presented here (ref; cell signaling).
Kinase Groupe
AGC
CAMK
CK1
CMGC
STE
TK
TKL

Description
Containing PKA, PKG, PKC families
Calcium/calmodulin-dependent protein kinase
Casein kinase 1
Containing CDK, MAPK, GSK3, CLK families
Homologue of yeast Sterile 7, Sterile 11, Sterile 20 kinases
Tyrosine kinase
Tyrosine kinase-like

Example 1 : Epidermal Growth Factor Receptor (EGFR)
Epidermal growth factor receptor (EGFR) exists on the cell
surface and is activated by binding of its specific ligands,
including epidermal growth factor and transforming growth
factor α (TGFα) Upon activation by its growth factor ligands,
EGFR undergoes a transition from an inactive monomeric form
to an active homodimer.
EGFR dimerization stimulates its intrinsic intracellular proteintyrosine kinase activity. As a result, autophosphorylation of
several tyrosine (Y) residues in the C-terminal domain of
EGFR occurs. This autophosphorylation elicits downstream
activation and signaling by several other proteins that associate
with the phosphorylated tyrosines through their own
phosphotyrosine-binding SH2 domains.
These downstream signaling proteins initiate several signal
transduction cascades, principally the MAPK, Akt and JNK
pathways, leading to DNA synthesis and cell proliferation.
Such proteins modulate phenotypes such as cell migration,
adhesion, and proliferation. Activation of the receptor is
important for the innate immune response in human skin. The
kinase domain of EGFR can also cross-phosphorylate tyrosine
residues of other receptors it is aggregated with, and can itself
be activated in that manner.
Role in human disease
Cancer
Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with
a number of cancers, including squamous-cell carcinoma of the lung (80% of cases), anal cancers, glioblastoma
(50%) and epithelian tumors of the head and neck (80-100%). These somatic mutations involving EGFR lead
to its constant activation, which produces uncontrolled cell division. In glioblastoma a more or less specific
mutation of EGFR, called EGFRvIII is often observed. Mutations, amplifications or misregulations of EGFR
or family members are implicated in about 30% of all epithelial cancers.

EGFR Kinase inhibitors
Epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER-1) inhibitors are either tyrosine
kinase inhibitors or monoclonal antibodies that slow down or stop cell growth.
EGFRs are transmembrane receptors present on the cell membranes. They have an extracellular binding
component, a transmembrane component and an intracellular tyrosine kinase component. EGFRs play an
important role in controlling normal cell growth, apoptosis and other cellular functions. Mutations of EGFRs
can lead to continual or abnormal activation of the receptors causing unregulated cell division, which can
account for some types of cancers.
Tyrosine kinase inhibitors bind to the tyrosine kinase domain in the epidermal growth factor receptor and stop
the activity of the EGFR.
Monoclonal antibodies bind to the extracellular component of the epidermal growth factor receptors, prevent
the actual substrates from binding to the receptors therefore prevent activation of the epidermal growth factor
receptor.
EGFR inhibitors are used to treat non-small-cell lung cancer, pancreatic cancer, breast cancer, colon cancer and
some other cancers that are caused by epidermal growth factor receptor up-regulation.
…… TO BE CONTINUED …..