Protein Kinase Targeting in Drug Development

Protein kinases comprise a vast family of enzymes that regulate virtually every aspect of cellular function by transferring a phosphate group from ATP to specific amino acid residues on substrate proteins. Dysregulation of kinase activity underlies numerous diseases, most prominently cancer, inflammatory disorders and neurodegeneration. Small-molecule inhibitors that target the conserved ATP-binding pocket have revolutionised therapy in several malignancies, yet challenges remain in achieving selectivity across the more than 500 human kinases. Resistance mutations, off-target toxicity and the dynamic conformational landscapes of kinases demand innovative strategies. Beyond ATP-competitive compounds, allosteric inhibitors and covalent binders offer routes to enhanced specificity and durable engagement. Advances in structural biology, notably high-resolution cryogenic electron microscopy, have illuminated previously intractable kinase complexes and revealed networks of water molecules and transient conformations that govern inhibitor binding. Complementary chemogenomic libraries and comprehensive profiling in live cells now guide the prioritisation of targets and predict clinical efficacy. The integration of structure-based design, systems-level selectivity profiling and an expanding toolkit of inhibitor types is redefining the drug-development paradigm for kinase-mediated diseases.

Research from Nature Portfolio

High-resolution cryo-EM studies have delivered atomic-level structures of the cyclin-dependent kinase-activating kinase both alone and in complex with a diverse set of inhibitors at up to 1.8 Å resolution. These structures elucidate intricate networks of water molecules within the active site and reveal subtle conformational shifts that dictate inhibitor selectivity, establishing a blueprint for the rational design of next-generation therapeutics. In parallel, the assembly and characterisation of a comprehensive kinase-inhibitor library has provided a well-annotated set of chemical probes that cover a broad swathe of the kinome. This resource underpins both target validation efforts and the discovery of novel binding modes for untargeted kinases, accelerating early-stage development and enabling more informed lead optimisation.

Protein Kinase Targeting in Drug Development publication trend

The graph below shows the total number of articles in protein kinase targeting in drug development across all publications each year (not limited to Nature Index journals).

Technical terms

Protein kinase: Enzyme that catalyses the transfer of a phosphate group from ATP to substrate proteins, modulating signalling pathways.

ATP-competitive inhibitor: Small molecule that occupies the ATP-binding pocket of a kinase, preventing phosphate transfer and halting downstream signalling.

Allosteric inhibitor: Compound that binds to regions outside the active site to induce conformational changes, thereby inhibiting kinase activity.

Cryogenic electron microscopy (cryo-EM): Imaging technique that freezes biomolecules and captures their structure at near-atomic resolution without necessitating crystallisation.

Kinome: The complete set of protein kinases encoded by an organism’s genome, representing the total kinase-target space for drug discovery.

References

1. High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design. Nature Communications (2024).
2. Comprehensive characterization of the Published Kinase Inhibitor Set. Nature Biotechnology (2016).
3. Kinase-targeted cancer therapies: progress, challenges and future directions. Molecular Cancer (2018).
4. Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement. Cell Chemical Biology (2017).