In Silico Exploration of Novel EGFR T790M and C797S Resistance with Mutant-Selective Allosteric Inhibitors Using a Hybrid Computational Approach

Tetrazole–imidazole hybrid derivatives as potential EGFR tyrosine kinase inhibitors: design, synthesis and in silico evaluation with preliminary antiproliferative assessment

Molecular modeling study on the binding mechanisms of third-generation EGFR inhibitor Lazertinib.

In recent years, in the treatment of non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) inhibitors have demonstrated ideal clinical efficacy. Unfortunately, a significant obstacle to targeted lung cancer therapy is the unavoidable emergence of acquired resistance to EGFR inhibitors through a variety of pathways during a period of medication. The third-generation EGFR inhibitor Lazertinib, which is potent, irreversible, brain-penetrant, mutant-selective, and wild type-sparing, was used to treat patients with advanced or metastatic NSCLC. Lazertinib can bind to EGFRT790M in different conformations, identified by a 180° rotation of the pyrazole moiety, according to the X-ray co-crystal structure. A molecular modeling study integrating molecular dynamics and free energy calculation was conducted to comprehend the distinct binding manner of Lazertinib binding to EGFR and the structural need for the inhibitory activity. According to binding free energy calculations, Lazertinib has a greater binding affinity with EGFRT790M than EGFRWT, which is in accordance with the experimental observations. Additionally, it confirms that Lazertinib preferentially binds to EGFRT790M with the same conformation as in EGFRWT. The residues that made a greater contribution to the binding of Lazertinib to EGFR were identified using the per-residue energy decomposition. It is anticipated that these findings will be helpful to the rational development of new EGFR inhibitors.

Structure-Based Design and Evaluation of Coumarin-Derived CDK4 Inhibitors for Non-Small Cell Lung Cancer: An Integrated Computational Study.

Findings establish coumarin-derived scaffolds as promising starting points for the development of next-generation CDK4-targeted therapeutics and provide a strong computational foundation for future experimental validation in NSCLC.

Towards better outcomes for epidermal growth factor receptor L858R+ lung cancer patients: mutant-selective allosteric inhibitors and the potential for double-drugging.

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a frequent cause of non-small cell lung cancer (NSCLC). Osimertinib, a third-generation tyrosine kinase inhibitor (TKI) that is selective for mutant EGFR, is standard of care for patients with the classical exon 19 deletion variants and the L858R point mutation. Although osimertinib and a recently developed therapy that combines TKI lazertinib with the antibody amivantamab improve outcomes for these patients, resistance limits the durability of response to these agents. Additionally, patients with the L858R mutation do not respond as well as those with exon 19 deletions, highlighting the need for more effective therapies for these patients and for those with brain metastases, a common complication of these cancers. In this review, we survey the development of next-generation EGFR inhibitors with a particular focus on allosteric inhibitors developed for L858R-mutant NSCLC. EAI-432 and other allosteric EGFR inhibitors can co-bind with osimertinib, offering the possibility of double-drugging the mutant receptor to achieve deeper and more durable responses for EGFR L858R+ patients. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.

Computational and Structure-Guided E-Pharmacophore-Based Virtual Screening for the Identification of Novel NEK2 Kinase Inhibitors as Potential Anticancer Agents

Allosteric co-binding restores tyrosine kinase inhibitor affinity in T790M-mutant EGFR through conformational reprogramming.

Drug resistance in epidermal growth factor receptor (EGFR)-mutant cancers commonly arises from kinase-domain substitutions that remodel the adenosine triphosphate binding pocket and reduce complementarity to orthosteric inhibitors, with the T790M gatekeeper mutation posing a major challenge. This study evaluated whether pre-occupying a proximal allosteric pocket with selected phytochemicals could bias mutant EGFR toward drug-compatible conformations and improve inhibitor binding. A two-phase computational workflow was employed: (i) molecular docking of gefitinib and erlotinib to wild-type and mutant EGFR; and (ii) allosteric pre-docking of phytochemicals followed by redocking of the ATP-site inhibitor. Top-ranked complexes were advanced to 200-nanosecond all-atom molecular dynamics simulations in explicit solvent and end-state binding free-energy estimation using Molecular Mechanics Generalized Born Surface Area (MM/GBSA). Docking predicted stronger binding to wild-type EGFR and reduced affinity for the T790M mutant, whereas co-binding produced compound-dependent improvements. Simulations suggested partial stabilization of the protein-ligand complexes, characterized by reduced root mean square deviation, damped hinge and αC-helix motions, reduced solvent exposure, and radii of gyration approaching wild-type behavior. Binding free energies improved from -12.6 to -17.6 kcal mol-1 (Genistein) and -19.58 kcal mol-1 (Tupichinols C) for gefitinib, and from -13.4 to -18.1 and -20.1 kcal mol-1, respectively, for erlotinib. Absorption, distribution, metabolism, excretion, and toxicity screening supported the developability of the leading candidates. This integrated framework provides structural, dynamic, and energetic criteria for prioritize cooperative allosteric-orthosteric co-binding chemotypes for experimental validation.