Tyrphostins
Encyclopedia
A tyrosine-kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinase
s, enzyme
s responsible for the activation of signal transduction
cascades (through phosphorylation
of various proteins). TKIs are typically used as anti-cancer drugs.
They are also called tyrphostins, the short name for “tyrosine
phosphorylation
inhibitor
”, originally coined in a 1988 publication, which was the first description of compounds inhibiting the catalytic activity
of the epidermal growth factor receptor
(EGFR).
The 1988 study was the first demonstration of a systematic search and discovery of small molecular weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinase
s that phosphorylate serine
or threonine
residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor
. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2.
agents and anti-leukemic
agents. Based on this work imatinib
was developed against chronic myelogenous leukemia
(CML) and later gefitinib
and erlotinib
aiming at the EGF receptor. sunitinib
, an inhibitor of the receptors for FGF
, PDGF
and VEGF
is also based on early studies on tyrphostins aiming at VEGF receptors
. It is estimated that about 30% of the current effort of the pharmaceutical industry is devoted to the development of protein kinase inhibitors, especially tyrphostins/TKIs.
(ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change
. Signal transduction therapy can in principle also apply for non-cancer proliferative diseases and for inflammatory conditions. Until now tyrphostins/TKIs have not been developed for the treatment of such conditions.
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s, enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s responsible for the activation of signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
cascades (through phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of various proteins). TKIs are typically used as anti-cancer drugs.
They are also called tyrphostins, the short name for “tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
”, originally coined in a 1988 publication, which was the first description of compounds inhibiting the catalytic activity
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
of the epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR).
The 1988 study was the first demonstration of a systematic search and discovery of small molecular weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s that phosphorylate serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
or threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
. It was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between even closely related protein tyrosine kinases such as EGFR and its close relative HER2.
Development of drugs
Numerous tyrphostins/TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumorTumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
agents and anti-leukemic
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
agents. Based on this work imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
was developed against chronic myelogenous leukemia
Chronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML) and later gefitinib
Gefitinib
Gefitinib INN , trade name Iressa, is a drug used in the treatment of certain types of cancer, particularly those with mutated and overactive EGFR. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor in target cells...
and erlotinib
Erlotinib
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
aiming at the EGF receptor. sunitinib
Sunitinib
Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...
, an inhibitor of the receptors for FGF
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
, PDGF
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
and VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
is also based on early studies on tyrphostins aiming at VEGF receptors
VEGF receptors
VEGF receptors are receptors for vascular endothelial growth factor . There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound or soluble , depending on alternative splicing.-VEGF:...
. It is estimated that about 30% of the current effort of the pharmaceutical industry is devoted to the development of protein kinase inhibitors, especially tyrphostins/TKIs.
Mechanisms
Tyrphostins operate by four different mechanisms: they can compete with adenosine triphosphateAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
. Signal transduction therapy can in principle also apply for non-cancer proliferative diseases and for inflammatory conditions. Until now tyrphostins/TKIs have not been developed for the treatment of such conditions.