foscenvivint (PRI724)

This study evaluated PRI-724, a CBP/β-catenin inhibitor, in patient-derived drug-naïve melanoma cells and their trametinib- or vemurafenib-resistant counterparts. The results of the study point to the potential of PRI-724 as a chemotherapeutic agent for the treatment of melanoma. Its efficacy might depend on CBP/β-catenin transcriptional activity in melanoma cells, and further evaluation of this signaling with survivin as a biomarker is therefore warranted.

To further dissect its mechanism, Wnt signalling was perturbed using siRNA against GSK3β, β-catenin and ICG-001 (a CBP/β-catenin interaction inhibitor), and their combination...This study identifies miR-195-5p as a potent regulator of CSCs and proliferation, and modulator of the Wnt signalling cascade. Co-inhibition of GSK3β and CBP/β-catenin through miR-195-5p highlights its therapeutic potential in combating stemness and proliferation in breast cancer.

This study demonstrates the functionality of SH3RF2 in both potentiating tumor progression and inducing M2 macrophage polarization through coordinated regulation of LZTS2 degradation and β-catenin nuclear translocation. These findings establish a novel mechanistic framework and propose SH3RF2-associated signaling axes as promising therapeutic targets for LUSC.

Pharmacological suppression of the β-Catenin pathway using ICG-001 established NF-κB as its downstream signaling mediator...FPN1 deficiency-induced iron overload exacerbates ROS production, triggering neuroinflammation, which may potentiate microglial activation and the IL-6/STAT3 pathway. The subsequent hepcidin-mediated iron sequestration reduces iron availability in the PFC and hippocampus, ultimately disrupting synaptogenesis and neuronal excitability, and culminating in depression-like behaviors.

Our study revealed that β-catenin activation drives sorafenib resistance in HCC, and disrupting β-catenin enhances sorafenib efficacy by promoting apoptosis and inhibiting proliferation. The combination of sorafenib and PRI-724, a Wnt/β-catenin inhibitor, showed synergistic anti-tumor effects in vitro across various HCC cell lines, in vivo using xenograft models, ex vivo utilizing MDT chip system to explore clinical applications, offering a novel therapeutic strategy for HCC patients.

Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies.

MITF and β-catenin levels were induced and treatment with Wnt/β-catenin inhibitor ICG-001 restored vemurafenib sensitivity with concomitant reductions in β-catenin-regulated gene expressions, phospho-ERK1/2, and VemR-induced mitochondrial mass and respiration. Pathways associated with cytokine-cytokine receptor, ECM receptor, and neuroactive ligand receptor interactions were similarly enriched in BRAFV600E patient-derived melanoma as M14 and A2058 cells whereas distinct pathways involving cell cycle, DNA replication, Fanconi anemia and DNA repair pathways are upregulated in wild type BRAF expressing patient derived melanoma. These data show for the first time that the metabolic pathway choices made by VemR BRAF mutant melanomas are controlled by vemurafenib tolerance and endurance thresholds and Wnt/β-catenin signaling plays a central role in coordinating expression of genes controlling VemR and metabolic pathway shifts.

Activation of the Wnt/β-catenin pathway mediates the high expression of PD-L1 to promote the resistance of NSCLC cells to icotinib. Thus, targeted inhibition of PD-L1 expression is of benefit for the treatment of NSCLC.

Pharmacologic interactions between EB and the Wnt signaling inhibitors IGC-011 and PRI-724 were determined by the combination index method and showed antagonism, indicating that EB acts on the same pathway as these inhibitors...Following exposure to human liver microsomes, EB was metabolized by NADPH-dependent oxidation and UDPG-dependent glucuronidation, as evidenced by the elimination of EB cytotoxicity against SCLC cells. Taken together, these data indicate that EB, a steroid hormone in plants consumed in the human diet, is pharmacologically active in drug-sensitive and drug-resistant SCLC cells in the Wnt signaling pathway, alters apoptotic gene expression, and is a substrate for microsomal modifications.

The Wnt inhibitor ICG-001 and PKM activator ML-265 inhibited ATRA-induced Neuro-2a and N1E-115 differentiation, whereas RNA interference-mediated Pkm silencing promoted Neuro-2a and N1E-115 differentiation, which was reversed by PKM overexpression...These results indicate that Wnt/β-catenin signaling promotes Neuro-2a and N1E-115 differentiation by inhibiting PKM-mediated glycolysis during ATRA-induced differentiation. These findings may provide a new theoretical basis for the role of glycolysis in nerve differentiation.

To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001...Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. Overall, the combined targeting of both the Hh/GLI1 and Wnt/β-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.