Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library
Autor: | Holly H. Soutter, Matthew A. Clark, Sevan Habeshian, Eric A. Sigel, Paolo A. Centrella, Diana Gikunju, Christopher D. Hupp, John W. Cuozzo, Anthony D. Keefe, Ying Zhang, Heather A. Thomson |
---|---|
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Plasma protein binding Biology 01 natural sciences Biochemistry Cell Line Chemical library Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Agammaglobulinaemia Tyrosine Kinase medicine Cytochrome P-450 CYP3A Humans Bruton's tyrosine kinase Binding site Protein Kinase Inhibitors Molecular Biology Binding Sites 010405 organic chemistry Organic Chemistry DNA Protein-Tyrosine Kinases Small molecule Protein Structure Tertiary 0104 chemical sciences Molecular Docking Simulation Kinetics 030104 developmental biology chemistry Mechanism of action biology.protein Molecular Medicine medicine.symptom Tyrosine kinase Protein Binding |
Zdroj: | ChemBioChem. 18:864-871 |
ISSN: | 1439-4227 |
Popis: | We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets. |
Databáze: | OpenAIRE |
Externí odkaz: |