Drug Design Midterm Assignment

Targeting Receptor Tyrosine Kinase

What are receptor tyrosine kinases?

Receptor tyrosine kinases (RTKs) are cell surface receptors that play an
essential role in signal transduction from extracellular stimuli. Receptor
tyrosine kinases are transmembrane proteins, which consist of several
domains that are activated upon ligand binding to their extracellular regions,
triggering downstream signaling cascades. They are involved in various
regulatory processes, such as cell survival, growth, differentiation, adhesion,
proliferation, and motility. Impaired gene functions by mutations or deletions
may cause the abnormal expression of protein kinases, which, in turn, entails
tumor formation and progression.

How are RTKs activated?

an un-activated RTK receptor encounters a ligand. Upon binding, the receptor

forms a complex of proteins that phosphorylate each other. In turn, this
phosphorylation affects other proteins in the cell that change gene
transcription.

RTKs as drug targets

RTKs as well as nonreceptor tyrosine kinase play a critical role in development
and cell growth, and a wealth of information has accumulated implicating
deregulated and dysfunctional RTKs in cancer and other diseases. Aberrant RTK
activation in human cancers is mediated by four principal mechanisms:
autocrine activation, chromosomal translocations, RTK overexpression, and
gain-of-function mutations.

Sequencing efforts in a wide variety of tumors have identified numerous

mutations in RTKs. Consequently, the focus has been to develop RTK
antagonists, rather than agonists which promote cell proliferation and survival.
Nonetheless, the discovery and development of RTK antagonists have lagged
behind the discovery and development of agents that target G-protein-coupled
receptors.

Several drugs have been developed for the treatment of cancers and other
diseases caused by aberrant RTK activation.

These drugs fall into two categories:

1. small-molecule tyrosine kinase inhibitors (TKIs) that target the ATP-

binding site of the intracellular TK domain
2. monoclonal antibodies that both interfere with RTK activation and target
RTK-expressing cells for destruction by the immune system

Two generations of small-molecule TKIs targeting RTK as well as nonreceptor

TK have been approved for the treatment of human malignancies since the
breakthrough with imatinib (is an oral chemotherapy medication used to treat
cancer)

A. First-generation TKIs like imatinib bind to their target, the catalytic site
in the TK domain, through classic competitive binding with ATP, and are
fairly selective for their respective TK targets.
B. Second generation of TKIs is now emerging and being introduced into
clinical trials. The two most commonly employed strategies are
introducing covalent (irreversible) binding of the drug to the RTK target,
and kinase multitargeting by broadening the affected RTK targets of the
drug within the cell. These novel TKIs appear promising as cancer
treatments, and these drugs attempt to improve upon their first-
generation predecessors.

Development of RTK agonists for pharmaceutical purposes has attracted

sparse interest due to the growth promoting actions and role in cancer
induction of many of the RTK family members. The IR is a special case among
the RTK in the since it has much more pronounced effects toward metabolic
responses, for example lowering of blood glucose. However, the discovery of
analogs of endogenous RTK ligands that possess partial agonist activity heralds
the possibility of clinically relevant ligand-based RTK antagonists. Endogenous
ligands for the ErbB RTK family, including the EGF receptor, function as partial
agonists which raised the possibility that they may act as antagonists with a
therapeutic potential in cancer treatment. The full and partial agonists for a
given ErbB receptor share a common binding site on that receptor. Thus, full
and partial agonists are expected to compete with each other for receptor
binding, and partial agonists are expected to function as competitive
antagonists of agonist-induced ErbB receptor signaling. Preliminary data have
shown that increasing concentrations of EGF partially antagonize stimulation of
EGF receptor coupling to cell proliferation by a fixed concentration of the EGF
receptor ligand amphiregulin. The partial agonist/antagonist paradigm may be
generally applicable to all RTKs raising the potential of developing a new
generation of RTK inhibitors based on their natural ligands.
Incorrect tyrosine kinase function can lead to non-small cell lung cancer. the
processes whereby RTKs are activated under normal physiological conditions
and discuss several mechanisms whereby RTKs can be aberrantly activated in
human cancers. Understanding of these mechanisms has important
implications for selection of anti-cancer therapies.

Tyrosine kinase inhibitors

Kinase inhibitors are now one of the major categories of chemotherapy
medicine.  Over 45 kinase inhibitors are approved in the US for cancer
treatment with more under development. Kinases are a class of enzyme that
promote phosphorylation. When these kinases go wrong, normal cellular
function can go awry. Kinase deregulation can contribute to the growth of
cancer. Drugs are given to stop kinases can slow the proliferation of malignant
cells and angiogenesis (growth of blood vessels). 
Tyrosine kinase inhibitors (TKIs) are a class of chemotherapy medications that
inhibit, or block, one or more of the enzyme tyrosine kinases. Some of the
receptors are enzymes and catalyze biochemical reactions.
Receptor Tyrosine Kinases (RTKs) are a family of tyrosine protein kinases. RTKs
span the cell membrane with an intracellular (internal) and extracellular
(external) portion. The intracellular portion removes a phosphate group, a
process called dephosphorylation, from the coenzyme messenger ATP. The
extracellular portion has sites to which signal sending proteins and hormones
can bind. Many of these signaling binders are growth factors.

Growth factors are involved in the initialization and regulation of cell cycles.
The type of growth factor determines its effects on the cell. There are three
primary growth factors that relate to tyrosine kinase. The receptors of these
growth factors are members of the RTK family. Epidermal growth factors (EGF)
help regulate cell growth and differentiation. Platelet-derived growth
factors (PDGF) regulates cell growth and development. Vascular endothelial
growth factors (VEGFR) are involved in the creation of blood vessels.
The growth factors, and the kinases, act together as though they are attached
to an “on/off” switch. The removal of a phosphate group changes the shape
and actions of the protein. This essentially “turns on” the cellular action (or
actions). When the cellular action(s) is completed, the phosphate group is
removed and that protein is “turned off.” This “on/off” process can become
disrupted, often by a mutated kinase, and actions can become unregulated. An
unregulated RTK bound to EGF, for example, could lead to uncontrolled growth
and division in the cell. The rapid cell growth could then lead to cancer.
Mutations of RTKs often lead to oncogenes, which are genes that help turn a
healthy cell into a cancerous cell.
Tyrosine kinase inhibitors treat cancer by correcting this deregulation.
Imatinib, for example, blocks a kinase receptor from binding to ATP, preventing
the phosphorylation that would benefit the cancerous cell and promote cell
division. Gefinitib inhibits EGFRs, preventing that signal from being stuck “on”
and creating uncontrolled proliferation.

References:
1. https://www.nature.com/scitable/topicpage/rtk-14050230/
2. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-
018-0782-4
3. Textbook of drug design and discovery 5th edition
4. https://chemoth.com/types/kinaseinhibitors