Kinase Inhibitor Drugs

Proteins are chains of amino acids and when a phosphoryl group, PO32−, is covalently linked to one of the acids, it changes the three-dimensional configuration and function of the protein.  Proteins are constantly being phosphorylated and dephosphorylated in living cells. Apoptosis, proliferation, and differentiation are all affected by phosphorylation, 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.

If medical intervention through drugs stops kinases, it can have positive effects on the growth of cancer.  There are many kinases and many kinase inhibitor compounds have been found. Some of these have proved to be useful in cancer treatment.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are a class of chemotherapy medications that inhibit, or block, the enzyme tyrosine kinase. TKIs were created out of modern genetics- the understanding of DNA, the cell cycle, and molecular signaling pathways- and thus represent a change from general to molecular methods of cancer treatment. This allows for targeted treatment of specific cancers, which lessens the risk of damage to healthy cells and increases treatment success.

To understand how TKIs function, one must look to the cellular level. The body can product up to 538 protein kinases,  Kinases are enzymes and some are “are associated with human cancer initiation and progression.”  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 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 thanks to 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. How this happens depends on the medication. Imatinib, for example, blocks a kinase receptor from binding to ATP, preventing the phosphorylation that would benefit the cancerous cell and promote cell division. The medication gefinitib (Iressa) inhibits EGFRs, preventing that signal from being stuck “on” and creating uncontrolled proliferation.

Over 30 TKI medications, including imatinib and gefinitib, have been approved by the Food and Drug Administration for use in humans. One TKI, toceranib (Palladia), was approved for the treatment of cancer in dogs. The human medications may inhibit one or more tyrosine kinases. Erlotinib (Tarceva),Erlotinib like gefitinib, inhibits EGFR. Lapatinib (Tykerb) is a dual inhibitor of EGFR and a subclass called Human EGFR type 2. EGFR isn’t the only growth factor targeted. Sunitinib (Sutent) is multi-targeted, inhibiting PDGFR and VEGF.

Other tyrosine kinase inhibitors are more specialized. Sorafenib (Nexavar) targets a complex pathway that would lead to a kinase signaling cascade. Nilotinib (Tasinga) inhibits the fusion protein bcr-abl and is typically prescribed when a patient has shown resistance to imatinib.

More TKIs are currently in development, though the process is slow and more drugs end up being abandoned during clinical phases than get approved.

Scientists are interested in TKIs because of their uniqueness compared to previous chemotherapy methods. All chemotherapy drugs seek to stop cell division and growth. They also attempt to kill cancerous cells without destroying the healthy cells. An inherent weakness in cancerous cells is that a failure of cell repair mechanisms is what turned the cells cancerous. The cell is therefore unable to repair damaged or changed DNA effectively.

Radiation therapy interferes with the DNA to create a problem the cancer cell cannot repair, leading to cell death. This interference can be done by modifying the building blocks, the bases, by adding to them to prevent bonding. Or it may be done through mechanical processes that separate the strands of DNA. These methods are rather non-specific, both in terms of the cancers they treat and the cells the act upon. This means that healthy cells may also pay the price of treatment.

Destruction of healthy cells is one of the main problems with traditional chemo treatments. TKIs, however, are targeted in that the different types can be cancer-specific, acting upon pathways that have gone awry in the specific cancer. Furthermore, it is often the case that the kinase itself is slightly different from the normal version, meaning that the inhibitor can work specifically on cancerous cells. The only other current treatment that works in a similar way is using monoclonal antibodies, which can also target cancerous cells in preference over healthy ones.

The specificity of TKIs results in fewer side effects and less time in the hospital needed for the patient. The genetic basis for cancers that can be treated with TKIs means it is feasible to screen biopsies and to administer treatment early in the disease progression.

Although kinase inhibitors are often used as part of a combination chemotherapy regimen, observers hope that clinicians will eventually be able to use kinase inhibitors without conventional chemotherapy drugs.  Because malignant cells grow quickly and consume a good amount of energy, scientists looked into whether intermittent fasting by the patient could control cancer growth.  Some scientific work shows that fasting plus administration of TKIs may be as effective as conventional chemotherapy without the side effects.

BTK Inhibitors

One type of tyrosine kinase is called Bruton’s tyrosine kinase.  It seems to be critical in development of parts of lymphoma and blood cells (mast cells and B cells).  Two drugs that inhibit this protein have been approved for cancer therapy:


BRAF inhibitors

BRAF is a gene that encodes creation of some growth factor enzymes – the enzymes are part of the system that tells cells how to differentiate, where to go, and when to die. If the BRAF gene mutates, it can result in cancer. (BRAF is an “oncogene”.) Scientists estimate 5 to 10 percent of human cancers involve a mutated BRAF gene.  BRAF mutations appear to be present in half of melanoma and papillary thyroid cancers, 3 percent of lung adenocarcinomas, and 10 percent of colorectal cancers.

Some kinase inhibitors affect enzymes made by the mutated BRAF gene.  Analysis of the biopsy tissue can tell whether a case has this mutation.  If so, that cancer is a candidate for BRAF inhibitor treatment.


Cyclin-dependent kinase inhibitors

Cyclin-dependent kinases are another type of proteins involved in the cell cycle.  There are 21 enzymes in this class and they are named sequentially – CDK-1, CDK-2, etc.

Compounds that inhibit these enzymes are under investigation for use as cancer treatments.  Some medicines are specific in targeting certain enzymes, e.g. CDK-4 inhibitor, while others are considered multi-CDK inhibitors.

When a cell starts to reproduce, it is CDK4 and CDK6  that are part of the biochemical cascade that starts that cycle.  CDKs are also involved in the transition from the G1 to M phase (CDK-2) and the G2 to S phase.(CDK-1).

Scientists have developed over 30 CDK inhibitors; this is one of the hottest areas in medicinal chemistry.  They are being investigated for treatment of cancer and other diseases including Cushing Disease and cystic fibrosis.  Three have been approved by the FDA for cancer treatment.

Abemaciclib (Verzenio) inhibits CDK-4 and CDK-6

Palbociclib (Ibrance) inhibits CDK-4 and CDK-6

Ribociclib (Kisqali) inhibits CDK-4 and CDK-6

MEK inhibitors

The oddly named mitogen-activated protein kinase kinase enzymes can be inhibited with drugs.  This action sees to slow the multiplication of cells. Scientists have developed some drugs to attack cancer through this mechanism.


Proteasome inhibitors

Proteasomes are physiolgical micostructures that are part of the body’s waste management system.  They break down old and unneeded proteins that the cells need to be rid of.  Compounds that stop or slow the action of the proteasomes are called proteosome inhibitors and scientists are looking at them as ways to fight cancer.  Some work so well the have gone through the drug development proccess and are approved for use against multple myelona.

Proteosome inhibitors have names that end in “zomib”

The FDA has approved these for cancer:


See also: Overview of Proteasome Inhibitor-Based Anti-cancer Therapies