Prolonged and tunable residence time using reversible covalent kinase inhibitors
| Autor: | Timothy D. Owens, Mary E. Gerritsen, Ronald J. Hill, David G Loughhead, J. Michael Bradshaw, Erik Verner, Dane Karr, David Michael Goldstein, Jesse M. McFarland, Vernon T. Phan, Angelina Bisconte, Vaishali Patel, Philip A. Nunn, Jens Oliver Funk, Jin Shu, David Finkle, Danny Tam, Tony Ton, Ken A. Brameld, Ville O. Paavilainen, Xiaoyan Li, Jack Taunton, Sergei Romanov |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Time Factors
Dasatinib Gene Expression Crystallography X-Ray Ligands Substrate Specificity Rats Sprague-Dawley Sf9 Cells Agammaglobulinaemia Tyrosine Kinase Cyanoacrylates B-Lymphocytes Tumor Crystallography biology Kinase Chemistry Protein-Tyrosine Kinases Small molecule Recombinant Proteins 3. Good health Cell biology Molecular Docking Simulation Biochemistry Fibroblast growth factor receptor Female medicine.symptom Tyrosine kinase Protein Structure Biochemistry & Molecular Biology Spodoptera Residence time (fluid dynamics) Article Cell Line Structure-Activity Relationship Medicinal and Biomolecular Chemistry In vivo Cell Line Tumor medicine Bruton's tyrosine kinase Animals Humans Molecular Biology Protein Kinase Inhibitors Acrylamides Cell Biology Protein Structure Tertiary Rats Thiazoles Pyrimidines Mechanism of action biology.protein X-Ray Sprague-Dawley Biochemistry and Cell Biology Tertiary |
| Zdroj: | Nature chemical biology, vol 11, iss 7 Nature chemical biology |
| Popis: | Drugs with prolonged, on-target residence time often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here, we demonstrate progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Utilizing an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrate biochemical residence times spanning from minutes to 7 days. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK more than 18 hours after clearance from the circulation. The inverted cyanoacrylamide strategy was further utilized to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating generalizability of the approach. Targeting noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates “residence time by design”, the ability to modulate and improve the duration of target engagement in vivo. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|