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  inhibit proliferation and angiogenesis. There are many kinases (538 in the human body) and many kinase inhibitor compounds have been found. Some of these have proved to be useful in cancer treatment.   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.

Scientists are looking the possibility of kinase inhibition for other diseases including hypertension and Parkinson’s disease but here we focus on cancer medicines.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are a class of chemotherapy medications that inhibit, or block, one or more of the enzyme tyrosine kinases.  Cell membrane receptors are what scientists call molecular structures that send and receive signals from the environment.  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.

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 Erlotinibfor the treatment of cancer in dogs. The human medications may inhibit one or more tyrosine kinases. Erlotinib (Tarceva), 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.

Serine and threonine kinases target serine and threonine residues rather than tyrosine residues on the DNA, and there are medicines that inhibit those enzymes, too.

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:

Acalabrutinib

Ibrutinib

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.

Vemurafenib

Dabrafenib

Sorafenib – considered both a BRAF inhibitor and a tyrosine kinase inhibitor

Regorafenib – considered both a BRAF inhibitor and a tyrosine kinase inhibitor

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

ALK inhibitors

The first ALK inhibitor, crizotinib, is now considered the first-generation of drugs in this class.  Crizotinib works on ALK and also on the pathways ROS1 and MET. In early tests scientists found this medicine inhibited the ALK pathway and that this pathway might be a good target for anti-cancer drugs.  Some (not all) patients with non-small cell lung cancer have a mutation in the ALK gene system.

The second generation of ALK inhibitors include ceritinib, alectinib, and brigatinib.  Other drugs are in development and lorlatinib was given orphan drug status by the FDA,   The drugs work on cells that have “chromosomal rearrangements” of ALK.

These are a form of personalized therapy.  The doctor can order a test of the biopsy tissue removed from the cancer.  If it indicates the malignant cells have the ALK mutation (are said to be ALK-positive), these inhibitors are thought to be a good potential form of treatment.

MEK inhibitors

One class of enzymes is the oddly named mitogen-activated protein kinase kinase (the double use of “kinase” is not a mistake, these are referred to as MAP2K, MEK, MAPKK.)  These catalyze phosphorylation of mitogen-activated protein kinase (MAPK). The MAPK pathway is a chain of reactions that transmit signals from the surface of the cell to the nucleus, and is important in how the body determines what proteins to make and when cells should divide.  The MAPK pathway is “dysregulated” in an estimated 50 percent of human cancers.  Scientists have developed drugs to inhibit these enzymes, and hence to slow the multiplication of malignant cells.

Cobimetinib

Trametinib

Advantages of Kinase Inhibitors

Scientists are interested in kinase inhibitors because they more precisely go after cancer cells than older chemotherapy methods. All chemotherapy drugs seek to stop cell division and growth. An inherent weakness in cancerous cells is that a failure of mechanisms to repair damaged or changed DNA effectively.

Destruction of healthy cells is one of the main problems with traditional chemo treatments. Kinase inhibitors, however, are targeted [LINK[ and act upon pathways that have gone awry in the specific cancer. This specificity results in fewer side effects and less time in the hospital for the patient. In many cases it is feasible to screen tumor biopsies to see if a particular patient’s cancer has a mutation that can be targeted by the drug.

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 kinase inhibitors may be as effective as conventional chemotherapy without as severe side effects.

Other inhibitor drugs