Recent advances in targeting p21-activated kinase 4 (PAK4) have unveiled transformative potential for therapeutic intervention, particularly in the realms of oncology and metabolic disease management. PAK4, a serine/threonine kinase within the PAK family, plays a critical role in cell signaling pathways governing cytoskeletal organization, cell survival, proliferation, and metabolism. Historically, research has primarily focused on PAK4 as a target in cancer due to its aberrant expression and oncogenic roles. However, emerging studies illuminate a pivotal function of PAK4 in metabolic regulation, heralding a new frontier in drug development aimed at combating obesity, type 2 diabetes, and fatty liver disease.
PAK4 inhibitors initially garnered attention through the development of multiple small molecules with varying degrees of potency and selectivity. Notable among these are PF-3758309, a pan-PAK inhibitor, and GNE-2861, a group II-specific PAK inhibitor. Despite their promising preclinical data, such agents faced setbacks when PF-3758309 exhibited unfavorable pharmacokinetics that halted its progress in early clinical trials. Meanwhile, KPT-9274, a dual inhibitor targeting both PAK4 and the nicotinamide phosphoribosyltransferase (NAMPT) enzyme, has progressed into phase I clinical trials against advanced solid tumors and lymphomas, underscoring a persistent interest in modulating PAK4 activity therapeutically even amidst challenges.
The quest for a selective, orally bioavailable PAK4 inhibitor capable of advancing into clinical stages remains critical. Addressing these gaps, the novel compound ND201651 emerges as a highly selective PAK4 inhibitor with favorable pharmacokinetic properties, warranting extensive evaluation in metabolic disorder models. Intriguingly, ND201651 has demonstrated profound efficacy in mouse models of obesity and metabolic syndrome, manifesting in significant weight loss that occurs independently of altered feeding or locomotor behavior. This decouples the metabolic benefits from changes in energy intake or expenditure, suggesting a direct mechanistic impact on metabolic pathways regulated by PAK4.
Pathophysiologically, ND201651 attenuates adipocyte hypertrophy and inflammatory macrophage infiltration within adipose tissue, crucial hallmarks of metabolic dysfunction. These anti-inflammatory and remodeling effects in adipose depots pave the way for enhanced systemic insulin sensitivity, as reflected in improved glucose tolerance tests. Further molecular analyses reveal upregulation of genes essential for fatty acid β-oxidation such as Cpt1a, Acox1, and Hmgcs2 following ND201651 administration, aligning with reduced hepatic lipid accumulation under dietary stress induced by both high-fat and ketogenic regimens. These findings position PAK4 inhibition as a multifaceted strategy directly remodeling metabolic tissue environments at the cellular and transcriptional levels.
Skeletal muscle, a major site of glucose disposal, also benefits significantly from PAK4 inhibition. ND201651 enhances glucose tolerance through an AMPK-dependent mechanism, promoting GLUT4 translocation to the plasma membrane and thus facilitating glucose uptake. Strikingly, such metabolic gains were absent in genetically engineered Pak4 knockout mice, confirming the specificity of ND201651’s pharmacological target engagement. This specificity differentiates ND201651 from less selective kinase inhibitors, highlighting the importance of precision targeting in therapeutic design to mitigate off-target effects and optimize metabolic outcomes.
Anticipating translational applications, the therapeutic potential of PAK4 extends beyond inhibition to targeted protein degradation strategies. Proteolysis targeting chimera (PROTAC) technology, which engenders selective degradation of target proteins, has been adapted effectively for PAK4. The first generation of peptide-based PAK4 PROTACs manifested robust anti-tumor efficacy in renal carcinoma models following intermittent intraperitoneal administration. Subsequently, second-generation PAK4-targeting PROTACs have demonstrated notable suppression of lung tumor metastases with systemic intravenous dosing, underscoring the therapeutic versatility of proteolytic strategies.
Capitalizing on these advancements, the PAK4-selective PROTAC SJ-05 has been developed as an oral agent derived from the ND201651 chemical scaffold. SJ-05 preserves the selectivity and bioavailability of its precursor while effectively degrading PAK4 protein upon oral administration in murine models. Notably, a ten-day oral regimen of SJ-05 in a sarcopenia mouse model successfully mitigated muscle atrophy, a metabolic complication with significant clinical burden. These data substantiate the concept that pharmacologically induced PAK4 degradation may provide superior or complementary benefits compared to traditional kinase inhibition, possibly due to sustained suppression of PAK4 signaling outputs.
While these therapeutic candidates mark significant milestones, several challenges remain on the path toward clinical translation. Crucially, the selectivity of inhibitors and degraders against closely related kinase family members such as PAK1 must be optimized to minimize unintended effects. Long-term safety profiles require thorough elucidation, particularly given the essential roles of PAK4 in normal cellular homeostasis. Comparative studies evaluating the efficacy and safety of kinase inhibition versus targeted degradation will be vital in defining optimal therapeutic modalities for PAK4-driven diseases.
Moreover, given the broad implications of PAK4 in diverse metabolic tissues—including liver, adipose, and muscle—future investigations should explore the systemic metabolic consequences of chronic PAK4 modulation. This holistic perspective is essential for addressing complex metabolic disorders characterized by multi-organ dysfunction. As these efforts advance, integration with existing therapies for obesity, diabetes, and fatty liver disease will be imperative to delineate the unique and additive benefits of PAK4-targeted strategies within current clinical paradigms.
In summary, the evolving landscape of PAK4 therapeutics is transforming from early pan-kinase inhibition attempts toward highly selective, orally bioavailable inhibitors and innovative PROTAC-based degraders. These breakthroughs promise to reshape therapeutic approaches to both cancer and metabolic diseases, integrating molecular precision with systemic metabolic correction. As the field moves forward, interdisciplinary research combining medicinal chemistry, metabolic biology, and clinical sciences will be paramount in harnessing the full potential of PAK4 modulation for patient benefit.
The promising efficacy of ND201651 and SJ-05 underscores the critical role of PAK4 in metabolic regulation and opens new avenues for designing next-generation drugs. Such agents not only confront obesity and insulin resistance mechanistically but also address pathological features such as fatty liver and muscle wasting, thereby offering comprehensive metabolic support. The dual capacity to inhibit enzymatic activity and induce protein degradation expands the therapeutic toolkit, potentially yielding tailored strategies for diverse patient populations and disease contexts.
Ultimately, the pursuit of selective PAK4 targeting aligns with broader trends in precision medicine, where detailed understanding of molecular signaling pathways informs rational drug design. The therapeutic nuances uncovered in recent studies highlight the intricate balancing act between efficacious target suppression and the maintenance of cellular homeostasis. By advancing PAK4 inhibitors and degraders through rigorous preclinical and clinical investigation, the scientific community edges closer to novel, impactful treatments for some of the most challenging metabolic disorders facing global health.
Subject of Research: PAK4’s role in metabolic diseases and its therapeutic targeting through selective inhibition and protein degradation.
Article Title: PAK4 in metabolic diseases: regulation by nutrient signals and therapeutic implications.
Article References:
Bang, I.H., Park, B.H. & Bae, E.J. PAK4 in metabolic diseases: regulation by nutrient signals and therapeutic implications. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01645-y
Image Credits: AI Generated
DOI: 10.1038/s12276-026-01645-y
Keywords: PAK4, metabolic disease, kinase inhibitor, PROTAC, obesity, diabetes, fatty liver, AMPK, GLUT4, fatty acid oxidation
Tags: dual PAK4 NAMPT inhibitionfatty liver disease treatmentGNE-2861 PAK inhibitorKPT-9274 clinical trialsmetabolic disease drug developmentobesity drug targets PAK4p21-activated kinase 4 therapyPAK4 inhibitors in diabetesPAK4 metabolic regulationPAK4 role in cell signalingPAK4 small molecule inhibitorsPF-3758309 pharmacokinetics
