Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation

Journal of Medicinal Chemistry
2010.0

Abstract

As a part of a study aimed at understanding how it is possible to take advantage of kinase structural elements to rationally guide compounds selectivity and improve type I and type II designs, an analysis of some recently published kinase inhibitors highlighted an additional kinase inhibitor design strategy. These compounds, which we classified as type I1/2 inhibitors, recognize the target kinases in the DFG "in" form. Type I1/2 compounds bind to the ATP site like type I compounds and extend to target the back cavity, establishing a defined set of conserved interactions with those residues characteristic of the type II design which is based on the DFG "out" form. Type I1/2 design could provide an additional tool in the rational design of compounds with the desired activity profile.

Knowledge Graph

Similar Paper

Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation
Journal of Medicinal Chemistry 2010.0
Rational design of inhibitors that bind to inactive kinase conformations
Nature Chemical Biology 2006.0
Comprehensive analysis of kinase inhibitor selectivity
Nature Biotechnology 2011.0
Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors
Journal of Medicinal Chemistry 2013.0
Structure-based design of isoindoline-1,3-diones and 2,3-dihydrophthalazine-1,4-diones as novel B-Raf inhibitors
Bioorganic & Medicinal Chemistry Letters 2011.0
DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity
Journal of Medicinal Chemistry 2020.0
Targeting Gain of Function and Resistance Mutations in Abl and KIT by Hybrid Compound Design
Journal of Medicinal Chemistry 2013.0
Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity
Bioorganic & Medicinal Chemistry 2015.0
Structure-Based Design of Potent Selective Nanomolar Type-II Inhibitors of Glycogen Synthase Kinase-3β
Journal of Medicinal Chemistry 2021.0
The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec®, Nexavar®, and BIRB-796
Bioorganic & Medicinal Chemistry 2010.0