Targeting kinases in neurodegenerative diseases and cancer: Structural insights and therapeutic strategies

Protein kinases play a key role in cellular signalling and are key drivers of neoplasia. In comparison, their role in neurodegenerative diseases used to be considered as secondary or downstream effects of neuronal damage. A growing body of data based on genetics, biochemistry, structural biology, and systems-level analysis has completely changed this view and placed kinase dysregulation as a common and unifying pathogenic pathway throughout cancer and neurodegeneration. The current chapter summarizes the recent progress that places kinases in a context-dependent state of molecular switches with disease-specific outcomes determined by structural conformation, spatiotemporal regulation, and network integration as opposed to kinase identity. The structural insights of high-resolution have changed the classical models that were based on pathways into models based on conformation and have shown that pathological kinase signalling is often caused by stabilisation of individual states of activity or regulation. These structural concepts describe the efficacy and drawbacks of first-generation ATP-competitive inhibitors, thereby leading to the development of allosteric, covalent, multi-target, and network-directed therapeutic approaches. The chapter also contrasts oncogenic kinase activation with oncogenic kinase dysfunction in post-mitotic neurons to demonstrate how the same signalling modules can be used to drive cell proliferation, cell survival, or cell degeneration depending on cellular context and microenvironment. The chapter also applies the knowledge in oncology, including mechanisms of resistance, adaptive signalling rewiring, and precision medicine, to neurodegenerative studies, but highlights the need for disease-specific adaptation due to the susceptibility and longevity of neurons.