MEK and the inhibitors: from bench to bedside
Akintunde Akinleye1, Muhammad Furqan, Nikhil Mukhi
1Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY 10595, USA. DELONG_LIU@NYMC.EDU.
Journal of Hematology & Oncology
|April 17, 2013
Summary
This review covers MEK inhibitors for cancer treatment, highlighting trametinib for melanoma and selumetinib
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mitogen-activated protein kinase (MAPK) signaling pathways are crucial in cellular processes.
- Seven MEK (MAPK/ERK kinase) enzymes regulate these pathways, with MEK1 and MEK2 being key members.
- Dysregulation of MAPK pathways is implicated in various cancers.
Purpose of the Study:
- To review the current landscape of MEK inhibitors in clinical development.
- To highlight specific MEK inhibitors and their therapeutic applications.
- To summarize emerging MEK inhibitors for cancer treatment.
Main Methods:
- Literature review of preclinical and clinical studies on MEK inhibitors.
- Analysis of data from clinical trials, including response rates and survival outcomes.
- Compilation of information on MEK inhibitors currently in clinical development.
Main Results:
- Trametinib is under FDA evaluation for metastatic melanoma with BRAF V600 mutation.
- Selumetinib demonstrated improved response rates and progression-free survival in combination with docetaxel for advanced lung cancer.
- Numerous novel MEK inhibitors are in various stages of clinical development.
Conclusions:
- MEK inhibitors represent a promising class of targeted therapies in oncology.
- Clinical trials are actively investigating the efficacy of various MEK inhibitors across different cancer types.
- The development pipeline for MEK inhibitors is robust, offering potential new treatment options for patients.
Related Concept Videos
01:30Enzyme Inhibition
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
01:15Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions
PK–PD modeling has significantly influenced FDA regulatory decisions, particularly drug approval, dosage optimization, and labeling. These models integrate pharmacokinetics (PK) and pharmacodynamics (PD) to predict drug behavior and effects, aiding in optimizing dosing regimens and enhancing the probability of clinical trial success.One notable example is Nesiritide (Natrecor®), a recombinant human brain natriuretic peptide for treating acute decompensated congestive heart failure (CHF).
02:04Protein-protein Interfaces
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...
01:16Protein-Drug Binding: Mechanism and Kinetics
Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...