Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles.
George Georghiou1, Ralph E Kleiner, Michael Pulkoski-Gross
1Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.
Nature Chemical Biology
|February 21, 2012
Summary
Macrocycles show high selectivity as protein kinase inhibitors, targeting Src kinase and its cancer-associated mutant. This research reveals their bisubstrate-competitive mechanism for potent and specific inhibition.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Molecular Pharmacology
Background:
- Protein kinases are key therapeutic targets, but their conserved nature hinders specific inhibitor development.
- Developing selective inhibitors for Src-family kinases, including the cancer-associated gatekeeper mutant, remains a challenge.
Purpose of the Study:
- To develop and characterize potent and highly selective macrocyclic inhibitors for Src kinase.
- To elucidate the molecular basis of inhibition and specificity for Src kinase and its mutants.
Main Methods:
- Screening of DNA-templated macrocycle libraries.
- Molecular characterization of identified inhibitors.
- Cocrystallography of macrocycles bound to Src kinase.
- Cell-based assays to assess Src activity inhibition.
Main Results:
- Identification of macrocyclic inhibitors with high selectivity for Src-family kinases.
- Cocrystal structures revealed a bisubstrate-competitive inhibitory mechanism (ATP and substrate peptide).
- Potent inhibition of Src kinase activity was observed in cultured mammalian cells.
Conclusions:
- Macrocycles can achieve potent and specific protein kinase inhibition via a bisubstrate-competitive mechanism.
- The study provides molecular insights into the specificity and efficacy of these macrocyclic Src inhibitors.
- These findings offer a foundation for developing novel Src-specific therapeutics for cancer.
Related Concept Videos
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...
01:03Single-Strand DNA Binding Proteins
For successful DNA replication, the unwinding of double-stranded DNA must be accompanied by stabilization and protection of the separated single strands of the DNA. This crucial task is performed by single-strand DNA-binding (SSB) proteins. They bind to the DNA in a sequence-independent manner, which means that the nitrogenous bases of the DNA need not be present in a specific order for binding of SSB proteins to it. The binding of SSB proteins straightens single-stranded DNA (ssDNA) and makes...
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...
02:53Conservative Site-specific Recombination and Phase Variation
Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
The recognition sites for Cre recombinase called LoxP...
02:57Targeted Cancer Therapies
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
There are several types of targeted therapies against specific...
01:26Targets for Drug Action: Overview
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...