Lead Optimization of Quinoline-Coumarin KRAS mRNA G-Quadruplex Ligands: Discovery of Non-Quaternary Ammonium Analogs as Translation Inhibitors.

Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRASG12C with Potent Antitumor Activity

Current KRASG12C inhibitors mainly target the inactive GDP-bound state, but clinical efficacy is limited, and resistance mechanisms have been identified. We disclose novel covalent inhibitors that selectively target the active GTP-bound KRASG12C. Starting from a high-throughput screen, we identified a keto-indolizine...

Design, synthesis, and structural optimization of novel pan-KRAS degrader for the treatment of KRAS-mutant pancreatic cancer.

KRAS, a frequently mutated oncogene, has been demonstrated to harbor multiple mutant variants. Although KRAS G12C inhibitors have been successfully approved for clinical use, their efficacy remains limited by acquired resistance and narrow patient eligibility. Here, we leveraged the proteolysis-targeting chimera (PROTA...

Structure-Based Design Strategies for Coumarin-Derived CDK4 Inhibitors in Non-Small Cell Lung Cancer: Current Progress and Therapeutic Perspectives

Exploiting Bridged Conformations for Precise Molecular Recognition in the Design of KRAS-Selective, Orally Available Macrocyclic Peptides

Macrocyclic peptides are attracting attention as a promising therapeutic modality for addressing intracellular targets that are traditionally difficult to address with conventional small molecules or antibodies. In this study, we present the chemical optimization process behind the development of AUBE00 (AP7400, comp...

Coumarin derivatives combating antibacterial resistance: molecular modeling-driven insights and comprehensive SAR elucidation targeting DNA gyrase and topoisomerase IV.

Antimicrobial resistance continues to threaten the effectiveness of current antibacterial therapies, creating an urgent need for novel chemotypes that act through alternative mechanisms. Among these, coumarin derivatives have emerged as promising inhibitors of bacterial type II topoisomerases, particularly DNA gyrase a...

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

Combined computational and preliminary cell-based findings support compound 4i as a promising lead for further investigation of EGFR-targeted anticancer activity and biochemical EGFR kinase inhibition and target-engagement studies are required to determine the mechanism of action.