Targeting PAK1 Within Group I PAKs: Current Challenges and Pharmacological Perspectives

The p21-activated kinase 1 (PAK1) has been investigated as a therapeutic target for more than two decades, particularly in cancer, where it contributes to cytoskeletal regulation, proliferation, survival, migration and therapy resistance. Despite the development of numerous potent inhibitors, selective pharmacological modulation of PAK1 remains difficult because of the high similarity of the group I PAK catalytic domains, especially PAK1 and PAK2, together with differences in conformational state, cellular localization and kinase-independent functions. This review examines PAK1 within the broader PAK kinase family and critically evaluates the principal pharmacological strategies developed to modulate its activity, including ATP-competitive and allosteric inhibition, targeted degradation, polypharmacology, combination therapies and indirect approaches. Recent structural studies indicate that local conformational differences between PAK1 and PAK2 can be exploited for improved isoform discrimination, while PAK1-selective degraders provide an alternative means of affecting both catalytic and non-catalytic functions. A snapshot analysis of current ChEMBL bioactivity data further shows that, although numerous compounds display high reported potency against PAK1, matched quantitative information for PAK2 and PAK3 is available for only a limited subset, leaving isoform selectivity unresolved for most compounds. Recent findings also position PAK1 within adaptive and treatment-resistance signaling rather than as a universal oncogenic dependency. Future progress will therefore depend not only on improving compound potency, but on integrating isoform profiling, cellular target engagement, structural information and disease-specific biomarkers to identify the settings in which PAK1 modulation can provide a meaningful therapeutic advantage.