MEK inhibitors Full-time Job

The first therapies to target this pathway were BRAF inhibitors, but intrinsic and acquired tumor resistance quickly led to treatment failure by reactivation of the MAPK pathway. MEK inhibitors have emerged to partially overcome these resistance mechanisms and are now used in combination with BRAF inhibitors to extend the time to resistance.

MEK is a dual specificity threonine/tyrosine kinase, so called from the term MAPK/ERK kinase. It is a key effector of the three-layered RAS/RAF/MEK/ERK signaling cascade, expressed by seven genes from MAPK1 to MAPK7.

MEK inhibitors bind to and inhibit MEK, inhibiting MEK-dependent cell signaling. This inhibition leads to cell death and the inhibition of tumor growth. These are allosteric binding inhibitors of MEK which inhibit either MEK1 alone, or both MEK1 and MEK2.

The MAPK pathway is an intracellular signaling cascade that is involved in the proliferation and survival of tumor cells. Many mutations cause cancer development by activating this pathway, including BRAF and NRAS mutations. MEK is a downstream protein kinase which can be targeted to prevent reactivation of the MAPK pathway in the presence of BRAF or RAS mutations.

Normally, ERK1/2 activation initiates a variety of cellular and nuclear pathways, while also inhibiting Raf activity by a feedback loop to modulate the activity of the MAPK pathway. MEK1/2 inhibition inactivates ERK1/2 and also removes the feedback inhibition on Raf.

Drugs which selectively inhibit the MEK enzymes are able to inhibit growth and to induce the death of cells in the presence of these mutations.

Thus, MEK1/2 is highly selective in inactivating ERK1/2 but leaves other signaling pathways intact. In addition, the non-ATP binding site means they do not typically need to compete with ATP, which is present in very large amounts inside cells. A new ATP-competitive inhibitor has also been designed which is effective in mutants that display drug resistance to the ATP-noncompetitive inhibitors.

Antineoplastic epidermal growth factor receptor (EGFR) inhibitors are a class of drugs used to treat hormone receptor-positive breast cancer (breast cancer that depends on hormones such as estrogen to grow), medullary thyroid cancer, advanced head and neck cancer, metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer.

EGFR inhibitors are anti-cancer medications that block the activity of a protein called EGFR. EGFR is found on the surface of some normal cells and is involved in cell growth, also found at high levels on some types of cancer cells, which causes these cells to grow and divide. Blocking EGFR helps in preventing unregulated cell division, thus preventing the growth, and spread of cancer cells.

EGFR inhibitors can be classified into the following:

Of the many proteins involved in cell cycle control, cyclin-dependent kinases (CDKs) are among the most important. CDKs are a family of multifunctional enzymes that can modify various protein substrates involved in cell cycle progression. Specifically, CDKs phosphorylate their substrates by transferring phosphate groups from ATP to specific stretches of amino acids in the substrates. Different types of eukaryotic cells contain different types and numbers of CDKs. For example, yeast have only a single CDK, whereas vertebrates have four different ones.

As their name suggests, CDKs require the presence of cyclins to become active. Cyclins are a family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them. CDKs must also be in a particular phosphorylation state — with some sites phosphorylated and others dephosphorylated — in order for activation to occur. Correct phosphorylation depends on the action of other kinases and a second class of enzymes called phosphatases that are responsible for removing phosphate groups from proteins.

How Do CDKs Control the Cell Cycle?

All eukaryotes have multiple cyclins, each of which acts during a specific stage of the cell cycle. (In organisms with multiple CDKs, each CDK is paired with a specific cyclin.) All cyclins are named according to the stage at which they assemble with CDKs. Common classes of cyclins include G1-phase cyclins, G1/S-phase cyclins, S-phase cyclins, and M-phase cyclins. M-phase cyclins form M-CDK complexes and drive the cell's entry into mitosis; G1 cyclins form G1-CDK complexes and guide the cell's progress through the G1 phase; and so on.

All CDKs exist in similar amounts throughout the entire cell cycle. In contrast, cyclin manufacture and breakdown varies by stage — with cell cycle progression dependent on the synthesis of new cyclin molecules. Accordingly, cells synthesize G1- and G1/S-cyclins at different times during the G1 phase, and they produce M-cyclin molecules during the G2 phase (Figure 2). Cyclin degradation is equally important for progression through the cell cycle. Specific enzymes break down cyclins at defined times in the cell cycle. When cyclin levels decrease, the corresponding CDKs become inactive. Cell cycle arrest can occur if cyclins fail to degrade.