Protein kinases function as key ‘control switches’ in cells, regulating growth, communication and responses to stress. While they have long been a central focus of drug development, most existing therapies are designed to inhibit kinase activity, particularly in cancer. However, in many common conditions, including cardiovascular, metabolic and neurodegenerative diseases, kinase activity is reduced rather than excessive. Safely restoring this activity has remained a significant scientific challenge.
In a study published in Cell (He et al Rational discovery of therapeutic PAK1 allosteric activators. https://doi.org/10.1016/j.cell.2026.03.008), an international team led by Professor Ming Lei from Department of Pharmacology at University of Oxford – working with collaborators across the UK, Germany, Poland, the United States and China – reports a new strategy (as illustrated in the figure above) to address this problem.
A major challenge in drug development lies in hit discovery, the initial stage of identifying small molecules that interact with a biological target to produce a desired effect. Conventional methods, particularly high-throughput screening (HTS), involve testing millions of compounds but are often inefficient in identifying suitable candidates.
To overcome this limitation, the researchers developed an approach termed Hit Discovery - Peptide Guided Strategy (HD-PGS). As illustrated in the second figure (above), this strategy integrates peptide-guided identification of regulatory (allosteric) sites with computational modelling, virtual screening, molecular docking and dynamics simulations, structural biology and functional assays. By focusing on allosteric sites, the approach enables more precise identification of compounds capable of modulating enzyme activity.
Central to the work is targeting autoinhibition, a natural self-regulatory mechanism that keeps many kinases inactive under normal conditions. By exploiting this mechanism, the team identified previously hidden control switch that can be used to activate enzymes.
The researchers applied this strategy to P21-activated kinase 1 (PAK1), an enzyme with an established role in cardiac function. Building on over two decades of research into PAK1’s involvement in calcium handling and cardiac electrophysiological stability, the team identified a previously unrecognised regulatory site using a peptide derived from the enzyme’s own sequence. They then designed small molecules that bind to this site and release the inhibitory constraint, and thereby activating the enzyme through an allosteric mechanism.
Experimental and computational studies showed that these molecules induce subtle structural changes that allow the enzyme to adopt its active form. Several compound series demonstrated strong activity, enhancing PAK1 signalling in both cellular and animal models. Activation of PAK1 produced beneficial effects in models of hypertrophic cardiomyopathy - conditions associated with heart failure and sudden cardiac death.
The researchers further demonstrated that the same strategy can be applied to other kinases, including protein kinase A (PKA), suggesting that the approach may be broadly applicable.
Professor Ming Lei, corresponding author of the study, said: “For many years, drug development has focused on inhibiting kinases. However, in a number of major diseases, the need is to restore or enhance their activity. By targeting the enzyme’s intrinsic regulatory mechanisms, we have established a practical strategy for designing kinase activators.”
Dr Yu He, joint first author, commented: “This approach is potentially applicable to a wide range of kinases, many of which are regulated through similar mechanisms. This opens new opportunities for therapeutic development.”
Dr James Bae, joint first author, added: “This work demonstrates how combining structural biology, computational modelling and pharmacology can uncover new drug targets that were previously inaccessible.”
This work provides both fundamental insight and a practical roadmap for developing a new class of drugs that activate protein kinases. This approach will open up new therapeutic possibilities for a range of diseases - including cardiovascular, metabolic, neurodegenerative and regenerative conditions - where current treatment options remain limited.
For a copy of the paper, click here: https://doi.org/10.1016/j.cell.2026.03.008