Related Experiment Video
Updated: Jun 15, 2026
07:16
Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues
Jeffrey W Lockman1, Matthew D Reeder, Kazuyuki Suzuki
1Department of Medicinal Chemistry, Myriad Pharmaceuticals, 305 Chipeta Way, Salt Lake City, UT 84108, United States. jeffrey.lockman@myriadpharma.com
Bioorganic & Medicinal Chemistry Letters
|March 2, 2010
Summary
Researchers synthesized thieno[2-3-b]pyridine analogues to inhibit eukaryotic elongation factor-2 kinase (eEF2-K). A key structural modification led to potent eEF2-K inhibition, with compound 34 showing significant activity.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biochemistry
Background:
- Eukaryotic elongation factor-2 kinase (eEF2-K) is a crucial regulator of protein synthesis.
- Dysregulation of eEF2-K is implicated in various diseases, making it a therapeutic target.
- Developing small molecule inhibitors of eEF2-K is an active area of research.
Purpose of the Study:
- To synthesize and evaluate novel thieno[2-3-b]pyridine analogues as potential inhibitors of eEF2-K.
- To identify key structural features responsible for eEF2-K inhibitory activity.
- To discover potent and selective eEF2-K inhibitors for further development.
Main Methods:
- Synthesis of diverse thieno[2-3-b]pyridine analogues.
- Screening of synthesized compounds for inhibitory activity against eEF2-K.
- Structure-activity relationship (SAR) studies to optimize lead compounds.
Main Results:
- Several series of thieno[2-3-b]pyridine analogues were successfully synthesized.
- A critical structural feature was identified as a ring fusion adjacent to the nitrogen on the thienopyridine core, which was essential for activity.
- Compound 34 emerged as the most potent inhibitor, exhibiting an IC(50) of 170 nM against eEF2-K in vitro.
Conclusions:
- Thieno[2-3-b]pyridine derivatives represent a promising scaffold for the development of eEF2-K inhibitors.
- Specific structural modifications, particularly the ring fusion, are critical for achieving high inhibitory potency.
- Compound 34 warrants further investigation as a potential therapeutic agent targeting eEF2-K.
Related Concept Videos
01:52Eukaryotic Transcription Inhibitors
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
01:20Antiepileptic Drugs: Potassium Channel Activators
Ezocgabine or retigabine, an antiepileptic drug of remarkable efficacy, has revolutionized the management of seizures. It is a potassium channel activator, explicitly targeting the family of Q subtype potassium channels. It enhances the transmembrane potassium currents, regulating neuronal excitability. This action stabilizes the resting membrane potential, a pivotal factor in mitigating the hyperexcitability that characterizes epilepsy.
Ezogabine has gained approval as an adjunctive treatment...
Ezogabine has gained approval as an adjunctive treatment...
01:15Antihypertensive Drugs: Thiazide-Class Diuretics
Thiazide diuretics are sulfonamide derivatives featuring a benzothiadiazine ring system in their molecular structure. Based on this structure, thiazide diuretics can be categorized into two groups: thiazide-type and thiazide-like diuretics. Thiazide-type diuretics, including hydrochlorothiazide and chlorothiazide, consist of a benzothiadiazine backbone with an attached sulfonamide group. Thiazide-like diuretics, such as chlorthalidone and indapamide, lack the thiazide ring but demonstrate...
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
01:28Inhibitors of Bacterial DNA Synthesis
Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
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.