Advancing Anticancer Therapies Through Molecular Hybridization Targeting Kinase Inhibition

Kinases remain among the most extensively pursued molecular targets in oncology drug discovery, given their central role in signal transduction pathways that govern cell proliferation, survival, and metastasis. Despite decades of progress, resistance mechanisms, off-target toxicity, and the structural similarity of the kinase catalytic domain continue to limit the long-term efficacy of many kinase inhibitors currently in clinical use. Molecular hybridization, which is the strategic fusion of two or more pharmacophoric units into a single chemical entity, has emerged as a powerful medicinal chemistry approach to overcome these limitations, offering the potential for improved potency, selectivity, and the ability to simultaneously engage multiple oncogenic targets or pathways.This Research Topic welcomes original research and review articles exploring the design, synthesis, and biological or computational evaluation of hybrid compounds with kinase-inhibitory activity relevant to cancer therapy. We particularly encourage submissions addressing rational hybridization strategies that combine kinase-targeting scaffolds with complementary pharmacophores, including but not limited to hybrids that engage additional oncology-relevant targets, disrupt tumor-supportive pathways, or address mechanisms of drug resistance.In addition to compounds purposefully designed as kinase inhibitors, we welcome studies of hybrid molecules that were not originally developed with kinase targeting in mind but were subsequently found, through biological or computational evaluation, to exhibit kinase inhibition or related activity. Such findings, whether arising from phenotypic screening, off-target profiling, structure-activity relationship studies, or in silico target-prediction approaches followed by experimental or in situ validation, offer valuable insight into unexpected structure-function relationships and may reveal new opportunities for scaffold repurposing or optimization.Topics of interest include, but are not limited to:o Design and synthesis of hybrid molecules incorporating kinase-inhibitory pharmacophoreso Structure-activity relationship studies clarifying how hybridization influences kinase selectivity and potencyo Computational and structural approaches (molecular docking, molecular dynamics, pharmacophore modeling) supporting hybrid compound design or the identification of unanticipated kinase activityo Biological evaluation of hybrid compounds in cancer cell lines, 3D culture systems, organoids, or in vivo modelso Mechanistic studies addressing how hybrid compounds modulate kinase signaling, drug resistance, or tumor microenvironment interactionso Repurposing or reprofiling of non-kinase-targeted hybrid scaffolds found to possess kinase-inhibitory or related activityo Hybridization strategies incorporating marine compounds and phytochemicals as kinase-targeting or complementary pharmacophoric units to overcome drug resistanceo Proof-of-concept studies bridging early discovery and preclinical development of kinase-targeting or kinase-active hybrid compoundsBy bringing together chemists, pharmacologists, and cancer biologists, this Research Topic aims to advance understanding of how molecular hybridization can be leveraged, whether by design or discovery, to develop next-generation kinase-modulating anticancer agents, while also illuminating the mechanistic basis of unanticipated kinase activity in hybrid chemical scaffolds.Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal. Topic editors: Cristian O. Salas, Abdulrahim A. Alzain, Guillermo Valdomir Source: https://www.frontiersin.org/research-topics/85410/advancing-anticancer-therapies-through-molecular-hybridization-targeting-kinase-inhibition