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Osimertinib is a covalent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (Exon19del or L858R), or with T790M resistance mutation following disease progression on first- or second-generation EGFR TKIs. The aim of this work was to understand how osimertinib achieves selective inhibition of mutant EGFR relative to wildtype through evaluating its kinetic mechanism of action. In doing so, we developed methodologies combining steady-state and pre-steady-state kinetics to determine the covalent inactivation rates (kinact) and reversible binding affinities (Ki) of osimertinib for WT, L858R and L858R/T790M EGFR, and compared these data to the inhibition kinetics of earlier generations of EGFR TKIs. The kinact/KI values indicate that osimertinib inactivates L858R and L858R/T790M with 20-fold and 50-fold higher overall efficiencies compared to WT, respectively. The Ki values reveal that osimertinib binds 3-fold and 17-fold tighter to L858R and L858R/T790M than to WT, respectively, while the kinact values show that osimertinib reacts 3-fold faster with L858R and L858R/T790M than with WT EGFR. We conclude that osimertinib achieves selective inhibition of L858R and L858R/T790M through improved affinities and improved rates of covalent bond formation via better positioning of the acrylamide warhead. This work highlights the importance of optimizing both reversible drug-target interactions and the inactivation rates for covalent inhibitors to achieve selectivity targeting mutant EGFR.
This article was published in the following journal.
Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). Howe...
Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) showing longer progression free survival and overall survival than other EG...
EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop ac...
Mutations in the gene that encodes epidermal growth factor receptor (EGFR) are biomarkers that predict how non-small cell lung cancer (NSCLC) patients respond to EGFR-targeted therapies collectively k...
Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.
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Phase II, single-arm study to assess the safety and efficacy of AZD9291 (80 mg, orally, once daily) in second-line (or later) patients with EGFR mutation-positive, locally advanced or meta...
YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild...
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To determine the feasibility and toxicity of neoadjuvant hypofractioned radiotherapy concurrently with weekly gemcitabine and an EGFR tyrosine-kinase inhibitor (OSI-774, Tarceva) in the tr...
A quinazoline derivative and ANTINEOPLASTIC AGENT that functions as a PROTEIN KINASE INHIBITOR for EGFR associated tyrosine kinase. It is used in the treatment of NON-SMALL CELL LUNG CANCER.
A protein kinase C subtype that was originally characterized as a CALCIUM-independent, serine-threonine kinase that is activated by PHORBOL ESTERS and DIACYLGLYCEROLS. It is targeted to specific cellular compartments in response to extracellular signals that activate G-PROTEIN-COUPLED RECEPTORS; TYROSINE KINASE RECEPTORS; and intracellular protein tyrosine kinase.
An eph family receptor found primarily in BRAIN and THYMUS. The EphB6 receptor is unusual in that its tyrosine kinase domain shares little homology with other members of this class. The unusual tyrosine kinase domain of this receptor appears to result in its lack of tyrosine kinase activity.
A receptor tyrosine kinase that is involved in HEMATOPOIESIS. It is closely related to FMS PROTO-ONCOGENE PROTEIN and is commonly mutated in acute MYELOID LEUKEMIA.
A tyrosine kinase inhibitor and ANTINEOPLASTIC AGENT that inhibits the BCR-ABL kinase created by chromosome rearrangements in CHRONIC MYELOID LEUKEMIA and ACUTE LYMPHOBLASTIC LEUKEMIA, as well as PDG-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors.
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...
GILOTRIF (afatinib) is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L8...