Hyperactivation of MAPK signalling is a common oncogenic event and is increasingly recognised to alter autophagy through sustained ERK1/2 activation, which can drive either pro-tumourigenic or anti-tumourigenic outcomes depending on cellular context. On this basis, ERK1/2 has emerged as an attractive therapeutic node, and several ERK inhibitors have advanced into clinical trial. However, their long-term effectiveness is frequently undermined by adaptive resistance, toxicity, and an incomplete understanding of how ERK suppression reshapes autophagic flux. These challenges highlight the need for new classes of ERK-targeting molecules that enable finer control over downstream signalling rather than indiscriminate pathway blockade.
In this work, we present the computational design and structural evaluation of a set of spirocyclic linked small molecules intended to modulate ERK1/2 activity and potentially influence autophagy in cancer cells. Spirocyclic scaffolds were chosen because they introduce threedimensional shape, restrict conformations, and often provide better physicochemical properties than traditional flat kinase inhibitors. We generated a focused virtual library of spirocyclic linked compounds and evaluated them using molecular docking based on highresolution ERK1/2 crystal structures. Our design approach emphasised strong interactions in the ATPbinding pocket, especially hingeregion hydrogen bonding while also exploring new spatial directions made possible by the spirocyclic linker core. Docking results were analysed to identify compounds that formed stable interactions with key catalytic residues. When compared with known ERK inhibitors, these spirocyclic candidates preserved essential binding features but also introduced unique threedimensional elements that could be useful for increased selectivity by the three-dimentional core and tuning autophagyrelated signalling. Collectively, this work establishes a rationally prioritised set of spirocyclic linked ERK1/2-inhbitor scaffolds and provides a strong computational foundation for subsequent chemical synthesis and biological validation aimed at developing next-generation autophagy-modulating anticancer agents.