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

Urea and carbamate-functionalized quinazolin-2,4-dione derivatives as EGFR tyrosine kinase inhibitors: synthesis, anticancer evaluation, molecular docking and molecular dynamics studies

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

A number of lead candidates with strong EGFR inhibitory potential, promising pharmacokinetic profiles, and mutant selectivity were successfully identified by the integrated computational approach.

Novel benzofuran-1,3,4-thiadiazole aryl urea hybrids as dual VEGFR-2/BRAF inhibitors: anticancer activity, apoptosis induction, and molecular modeling studies.

A novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template, with compound 7j emerging as the most active analogue.

VEGFR-2 as a druggable target: recent advances (2025) in the development of five-membered heterocyclic anticancer agents.

The global burden of cancer continues to escalate, with angiogenesis representing a critical driver of tumor progression and metastasis. Vascular endothelial growth factor receptor-2 (VEGFR-2) stands as the principal mediator of angiogenic signaling, making it an established and compelling therapeutic target. Despite the clinical success of first-generation inhibitors, their long-term efficacy remains limited by off-target toxicities, suboptimal pharmacokinetic profiles, and the inevitable emergence of drug resistance through multiple adaptive mechanisms. These limitations underscore an urgent need for next-generation inhibitors engineered with enhanced selectivity, improved safety margins, and the capacity to circumvent resistance pathways. This comprehensive review systematically examines recent advances in the rational design, synthesis, and biological evaluation of five-membered heterocyclic scaffolds, thiadiazol, oxazole, thiazole, and pyrrole, as well as pyrazole and imidazole-based inhibitors as novel VEGFR-2 inhibitors. Each section analyzes the molecular hybridization strategies employed to integrate essential pharmacophoric features, including heteroaromatic hinge-binding motifs, hydrogen bond donor-acceptor systems for DFG motif engagement, and terminal hydrophobic groups for allosteric pocket occupancy. Detailed structure-activity relationship discussions elucidate how substituent variations influence potency, selectivity, and physicochemical properties.

EGFR-Targeted Amino Quinoxaline Derivatives as Potential Anticancer Interventions: In Silico Design and in Vitro Evaluations

The Epidermal Growth Factor Receptor (EGFR) remains validated therapeutic goalfor Breast Cancer, especially because of its function in signalling pathways that promote tumor development and viability. In the current investigation, a series of newly designed amino quinoxaline derivatives (QN1–QN10) were investigated for their potential EGFR inhibitory and anticancer activities using an integrated in silico and in vitro approach. Molecular docking studies were carried out using Schrödinger Maestro to rate the binding kineticsof the designed compounds with the EGFR tyrosine kinase domain (PDB ID: 4HJO), employing erlotinib as the reference standard. The docking protocol was validated by redockingerlotinib into the active site, confirming the reliability of the methodology. Glide extra-precision (XP) docking revealed favourable binding orientations of selected derivatives within the EGFR catalytic pocket. The cytotoxicity of selected compounds (QN2, QN4, and QN8) was further calculated through MTT assay for human breast cancer cell line MCF-7. The results proved that the cell longevity was decreased in a concentration-dependent way, with erlotinib exhibiting the greatest potency (LC50 = 18.47 µg/mL). Among the synthesized derivatives, QN4 showed relatively higher activity (LC50 = 121.52 µg/mL) than QN2 and QN8.Statistical analysis proved the relevance of the cytotoxic effects observed (p < 0.0001). Overall, the combined computational and biological findings suggest that amino quinoxaline scaffolds indicate potential avenues for enhanced optimization as EGFR-targeted anticancer drugs.

Design, synthesis, antitumor estimation, and molecular docking of new imidazothiazolediones as potential dual EGFR and IDO1 inhibitors and apoptosis stimulators.

A novel set of imidazo[2,1-b]thiazolediones 4a,b and 5a-d, with anticipated EGFR and IDO1 inhibition activities, was designed and prepared. These novel derivatives were evaluated in the NCI 60 cell line panel in which the superior compounds 5b and 5d were chosen for further evaluation of their five dose cytotoxicity toward the most sensitive cancer cells namely non-small cell lung cancer EKVX and HOP-92, breast HS 578 T, and normal WI-38 cells. The presence of a substituted benzylidene moiety at position-2 of the imidazothiazole scaffold in compounds 5a-d positively influences anticancer activity, with the phenylallylidene moiety at position-6 exhibiting superior cytotoxic effects compared to the 2-thienylidene moiety. Among the examined hybrids, 5d showed significant antiproliferative effect against HS 578 T tumor cell. To explore the underlying cell-death mechanisms, secondary biological evaluations were conducted, including cell-free EGFR and IDO1 enzymatic inhibition, apoptosis assay, and cell cycle analysis. In cell-free biochemical assays, the most active derivatives demonstrated a promising potential dual inhibitory profile against EGFR and IDO1, with compound 5d exhibiting sub-micromolar activity against both target enzymes, providing a plausible biochemical rationale for its potent cell killing. Furthermore, compound 5d induced cell cycle arrest at the G2/M phase and triggered apoptosis in HS 578 T cells, as supported by the up-regulation of Caspase-3 and Bax accompanied by the down-regulation of Bcl-2. In-silico ADMET profiling and molecular docking simulations further supported the favorable drug-like properties and binding modes of the key compounds within the target active sites. Overall, these findings highlight compound 5d as a promising lead candidate for further optimization and cellular mechanistic validation in anti-cancer drug discovery.