Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Year: 2022
Type: article
Abstract: Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.
Source: Nature Communications
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: G1851145110, G33335446, G4824040786, Pixel Array Detector for Macromolecular Crystallography, G5384392517, Studies of mutant-selective allosteric inhibitors of EGFR for non-small cell lung cancer, G601477287, G604848185, G63963844, G6692454511, Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma, G7142111803, G7395550650, NE-CAT Center for Advanced Macromolecular Crystallography, G764133772, G9000020627, G9000038451, G9000046420, G9000165225, G9000348095, Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G9320746
OpenAlex ID: W4229367563