PAK4 (P21 (RAC1) Activated Kinase 4)

Furthermore, inhibition of PAK4 kinase activity promotes GEM-induced suppression of pancreatic cancer growth both in vitro and in vivo. Our study suggests that targeting PAK4 to promote GEM-induced pyroptosis may provide a new therapeutic approach for the treatment of pancreatic cancer.

Among the synthesized compounds, 17 (PAK4 IC₅₀ 0.71 μM) and 29 (PAK4 IC₅₀ 1.88 μM) demonstrated comparable enzymatic potency, consistent with ATP-competitive inhibition, while compound 29 was effective in inhibiting cancer cell proliferation (HCT-116 GI₅₀ 23.0 μM; A549 GI50 11.3 μM). In conclusion, this study highlights the potential of targeting underexplored subpockets in PAK4 and provides new molecular insights for the discovery of PAK4 inhibitors.

PAK4 is significantly overexpressed in ACC, and it may play a carcinogenic role, showing great application potential as a potential therapeutic target and an independent prognostic biomarker of ACC.

This review outlines the osteoblast-specific signaling pathways of PTH (1-34) and includes our recent research that identified p21-activated kinase 4 as a downstream effector linking canonical cyclic adenosine monophosphate-protein kinase A signaling to Wnt/β-catenin activation. Additionally, it explores the potential implications of PTH (1-34) in the context of breast cancer-related bone metastasis.

Consistent with these findings, preadipocyte-specific Pak4-knockout mice exhibited reduced fat mass and smaller adipocytes. These results reveal PAK4 as a crucial regulator of adipogenesis and, together with its inhibitory role in triacylglycerol lipolysis, further underscore its potential as a therapeutic target for obesity treatment.

Combining the PAK4 inhibitor KPT-9274 with the MCL-1 antagonist S63845 induces synergistic lethality in AML cells. These findings provide the mechanistic insight of MYC stabilization in AML and establish a PAK4 inhibition-based targeted strategy as a promising therapeutic approach for AML treatment.

Furthermore, the small-molecule inhibitor MLN4924, which blocks NEDD8-activating enzyme, reversed the degradation of POLR2A/B/E, supporting the role of ubiquitin-proteasome pathways in this process. Functional assays confirmed that PF-3758309 inhibits tumor cell growth and migration by promoting ubiquitination-dependent degradation of POLR2A/B/E. These findings uncover a previously unrecognized mechanism of PF-3758309's anti-tumor activity and provide a basis for further investigation into its therapeutic potential.

We propose that the MASTL/YBX1/PAK4 axis, which is activated by stress-induced STK24, plays a crucial role in lenvatinib tolerance. Inhibiting this axis by targeting MASTL effectively overcomes lenvatinib resistance in HCC.

Our study demonstrates that PAK4-high/NAMPT-high pNENs are associated with distinct molecular and immune profiles. Further investigation is warranted to determine if dual PAK4 and NAMPT blockade enhances the efficacy of immunotherapeutics.

Finally, we tested the combination therapy in mouse intracranial graft tumor models and found that combination therapy can prolong mouse survival. These findings suggest that anti-VEGFR2 therapy can downregulate PAK4, reprogram the TME by increasing cytotoxic CD8+ T cells infiltration and activation, and enhance the therapeutic effect of anti-PD-L1 therapy on GBM cells.

In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.