Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC₅₀ values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC₅₀ value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC₅₀ of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.

Targeting of cyclooxygenase-2 (COX-2) has emerged as a powerful tool for therapeutic intervention because the overexpression of this enzyme is synonymous with inflammation, cancer, and neurodegenerative diseases. Herein, a new series of 1,2,4-triazole Schiff bases scaffold with aryl and heteroaryl systems 9a–12d were designed, synthesized, structurally elucidated, and biologically evaluated as a potent COX-2 blocker. The rationale beyond the current study is to increase the molecule bulkiness allowing a selective binding to the unique hydrophobic pocket of COX-2. Among the triazole–thiazole hybrids, the one with the para-methoxy moiety linked to a phenyl ring 12d showed the highest In vitro selectivity by COX-2 inhibition assay (IC₅₀ of 0.04 μM) and in situ anti-inflammatory activity when evaluated using the protein denaturation assay (IC₅₀ of 0.88 μM) in comparison with commercially available selective COX-2 inhibitor, Celecoxib (IC₅₀ of 0.05 μM). Towards the COX-2 selectivity, ligand-based three dimensional quantitative structures activity relationship (3D-QSAR) employing atomic-based and field-based approaches were performed and resulted in the necessity of triazole and thiazole/oxazole scaffolds for COX-2 blocking. Furthermore, the molecular modeling study indicated a high selectivity and promising affinity of our prepared compounds to COX-2, especially the hydrophobic pocket and the mouth of the active site holding hydrogen-bonding, hydrophobic, and electrostatic interactions. In Silico absorption, delivery, metabolism, and excretion (ADME) predictions showed that all the pharmacokinetic and physicochemical features are within the appropriate range for human use.

Targeting VEGFR2, compound 4e and its Fe ₂ O ₃ -humic acid-NPs could be further developed as promising anti-breast cancer agents.

Background/Objectives: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2/c-Met inhibitors. Methods: The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. Results: Compounds 5a, 5g, 5h, 11a, and 11b showed strong inhibition of both kinases (IC₅₀ = 0.145–0.970 μM for VEGFR-2 and 0.181–1.885 μM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound 11b (p-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, 11b induced G₂/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. Conclusions: Compound 11b was established as a novel, selective, dual VEGFR-2/c-Met inhibitor with strong potential for targeted breast cancer therapy.

Overexpression of epithelial growth factor receptor (EGFR) has been identified as the driving mechanism within the development and progression of several cancers. The emergence of resistance induced by mutations in the EGFR gene has presented a formidable challenge in the development of new EGFR inhibitors. Guided by the pharmacophoric features of EGFR inhibitors, a new series of quinoline–hydrazone hybrids (4–15) were rationally designed, synthesized, and pharmacologically evaluated against liver HepG-2 and breast MCF-7 cancerous as well as normal mammary gland epithelial cell lines. Compounds 13–15 showed low-to-sub micromolar inhibitory activities (IC₅₀ = 0.98 ± 0.03 to 7.37 ± 0.69 μM) for the studied cell lines, while compound 14 exhibited a safety profile against normal cells. Moreover, significant selectivity indices were also depicted for compound 14 against two mutant EGFRs (T790M and L858R) in relation to the wild-type form. Molecular aspects of compound–target binding were postulated through valid molecular modelling studies on both wild-type and mutant EGFRs. Additionally, the drug-likeness and clinical candidacy of the three top-active compounds were evaluated through comprehensive computational tools of pharmacokinetic/ADMET profiling and mutagenicity prediction. Embarking on improving the compound's pharmaceutical properties, three different metal-based nanoparticle formulations (silver, selenium, and cobalt tetraoxide) for compound 14 depicted enhanced cytotoxicity compared to the parent compound. These findings revealed compound 14 as a promising anticancer lead candidate with prospects for future optimization and development.