PAK1 (p21 (RAC1) activated kinase 1)

Importantly, our results revealed that the PAK1 inhibitor, PF3758309, exhibited a profound synergistic effect with oxaliplatin in CRC. Collectively, our study unveils a novel function of PAK1 in CRC progression. Thus, these results highlight the potential of targeting PAK1 as a therapeutic strategy in CRC, particularly in combination with oxaliplatin.

p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC50 = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.

These data support the hypothesis that inhibition of PAK1 confers dendritic spine resilience against Aβ and tau oligomers in early-stage preclinical models. Ongoing oncology clinical trials assessing effects of PAK1 inhibitors point to the possibility of testing PAK1 inhibitor approaches in AD trials.

Elucidating the mechanistic links between PAK1 and the Warburg effect unveils novel opportunities for targeted cancer therapies aimed at disrupting metabolic vulnerabilities. An ideal biodegradable drug delivery system and an appropriately representative pre-clinical model exploiting the Warburg effect could enhance targeted delivery and therapeutic efficacy, and could help advance tumor targeted therapies in aggressive cancers like TNBC and pancreatic cancer.

USP33 silencing increased the drug sensitivity of PC in vivo. METTL3 supports GEM resistance of PC cells partly by regulating USP33-mediated PAK1 deubiquitination, providing a promising therapeutic target for GEM-resistant PC cells.

However, the P29S mutation severely impairs p50GAP-mediated hydrolysis, leading to accumulation of RAC1P29S in its GTP-bound state and loss of temporal regulation. This persistent activation hyperactivates downstream effectors and promotes cancer-associated pathways, including ERK and p38 MAPK, which drive cell growth, survival, invasion and metastasis.

While no significant difference was found in PAK1 protein levels in plasma samples (p > 0.05), it was found to be lower in urine samples of patients compared to the control group (p = 0.00). Both marker molecules have low expression levels in early-stage PCa.

Both PAK1fl and PAK1CKO mice were more resistant to shifts in microbiome, and remained clustered together compared to WT or PAK1KO. Altogether, our results suggest that floxing itself may have altered Pak1 expression, which conferred protection from AOM/DSS carcinogenesis.

This study demonstrates that PUM1 enhances the RNA stability of PAK6, thereby contributing to ferroptosis resistance in LUAD cells.

YAP1::MAML2 fusions were also detected in the two tumors with panfollicular differentiation. In conclusion, we report six cases of follicular tumors with YAP1::MAML2, YAP1::NUTM1, or RNF13::PAK2 fusions and therefore suggest that in addition to poroid tumors, YAP1 and PAK2 fusions might be the oncogenic driver in a subset of adnexal tumors with prominent follicular differentiation.

Furthermore, OPC proliferation and intra-lesional repopulation are significantly impaired in mice of OPC-specific PAK1 deletion or kinase inhibition after white matter injury. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a proliferative progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.

A structure-based design effort targeting a PAK1 (over PAK2) selective small molecule inhibitor is detailed herein. We report here the first crystal structure of PAK2 and use this crystal structure to design a PAK1 inhibitor with ten-fold selectivity over PAK2.