Charting the evolving landscape of kinase hinge-binding chemotypes beyond flatland: a systematic analysis and...

ATP-competitive kinase inhibitors represent one of the most successful modalities in targeted therapy, yet their discovery has historically relied on a narrow repertoire of hinge-binding motifs. Here, we report a large-scale structural analysis of 4370 kinase-ligand complexes spanning 289 human protein kinases, providing the most comprehensive publicly available catalogue of hinge-binding scaffolds to date. Systematic extraction and consolidation identified 846 unique hinge binders, enabling quantitative assessment of their frequency, promiscuity, and residue interactions across the kinome. The analysis reveals that hinge binders remain predominantly planar heteroaromatic chemotypes, and that progress over the past three decades has largely involved incremental optimization of these limited motifs rather than exploration of sp³-enriched scaffolds. Novel opportunities for chemical innovation were identified through noncanonical interactions, such as halogen bonding, as well as through conformationally restricted designs, including macrocycles to generate sp³-enriched hinge-binding moieties. Although limited in number, these examples demonstrate that nonplanar chemotypes can achieve hinge engagement comparable to that of rigid planar binders while substantially expanding the accessible chemical space of kinase inhibitors. Collectively, this work delineates the structural landscape of kinase hinge binders and provides a hinge-binding resource to enable scaffold hopping and focused library design, while identifying opportunities for the discovery of next-generation ATP-competitive kinase inhibitors within a highly competitive therapeutic space.