BMS-345541

Glioblastoma (GBM) is one of the most aggressive and fatal cancers, for which Temozolomide (TMZ) chemo drug is commonly used for its treatment. The ADMET analysis of this drug BMS345541 shows a higher half-life and lower cytotoxicity level than other predicted repurposed drugs. Hence, we conjecture that this could be a better drug for increasing the sensitivity of TMZ for treating GBM patients.

In the high-risk group, erlotinib showed higher IC50 values compared to the low-risk group which exhibited higher IC50 values for VX-11e, AKT inhibitor VIII, AT-7519, BMS345541, Bortezomib, CP466722, FMK, and JNK-9L. The results of RT-qPCR revealed that the expression of four UEGs was higher in tumor tissue as compared to normal tissue. Based on the genes that were expressed differently and associated with ubiquitination-related tumor categorization, we have developed a pattern of four genes and a strong nomogram that can predict the prognosis of HCC, which could be useful in identifying and managing HCC.

Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias...Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib...Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.

In in vitro drug screening, BMS-345541 demonstrated efficacy as a therapeutic targeting of CDKN1B, effectively impeding the growth of breast cancer cells characterized by low CDKN1B expression. The inclusion of CDKN1B expression in GBM models increased the accuracy of survival predictions. CDKN1B expression plays a significant role in breast cancer progression, implying that targeting CDKN1B might be a promising strategy for treating breast cancer.

Aims: To assess whether inhibition of NF-κB and/or JAK/STAT signaling can attenuate the inflammatory state and reverse the MF-like phenotype in an aged miR-146a -/- mouse model, using either (a) the JAK1/2 inhibitor ruxolitinib (RUX), (b) the NF-κB pathway inhibitor, through IKKα/β, BMS-345541 (BMS), (c) RUX+BMS, or (d) the dual JAK2/IRAK1 inhibitor pacritinib (PAC). In an aging-associated MF-like murine model without driver mutations, NF-κB inhibitors, either alone or incombination with JAK inhibitors, as well as dual-acting inhibitors, reduced inflammatory cytokines and splenomegaly, reversed thrombocytopenia and improved BM fibrosis. The combination therapy (RUX+BMS) produced BM aplasia and worsened anemia, whereas the dual inhibitor (PAC) improved or stabilized hematologic parameters. Bone Marrow Fibrosis, Myelofibrosis, NF- B, Myeloproliferative disorder

11-month-old miR-146a-/- mice were 1-month-oral ad libitum treated with either ruxolitinib (JAK1/2 inhibitor) at 75 mg/kg/day, BMS-345541 (BMS) (NF-κB pathway inhibitor at IKKα/β level) at 100 mg/kg/day, both inhibitors at the same concentrations, or pacritinib (JAK2 and NF-κB pathway inhibitor at IRAK1 level) at 150 mg/kg/day. miR-146a-/- mice constitute a useful model of MPN without driver mutations to evaluate the role of inflammation in these neoplasms. The dual inhibition of NF-κB and JAK/STAT with pacritinib reduced inflammatory cytokines, reverted monocytopenia and thrombocytopenia, and improved BM fibrosis without worsening anemia. While some of these benefits could be recapitulated in vivo by combining ruxolitinib with an NF-κB inhibitor, this combination resulted in worsening anemia and BM aplasia.

In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.

Our data demonstrate that IGFBP3, a potential biomarker for radiosensitivity, promotes IR-mediated OSCC cell death by increasing ROS production through NF-κB activation and cytokine production.

Our findings indicate, for the first time, that Calebin A chemosensitizes human CRC cells to chemotherapy by targeting of the p65-NF-κB signaling pathway.

The 3D-alginate HCT116 cell cultures in TME were treated with Calebin A, BMS-345541, and dithiothreitol (DTT) and examined for invasiveness, proliferation, and apoptosis...Calebin A also suppressed the expression of NF-κB-promoted anti-apoptotic (Bcl-2, Bcl-xL, survivin), proliferation (Cyclin D1), invasion (MMP-9), metastasis (CXCR4), and down-regulated apoptosis (Caspase-3) gene biomarkers, leading to apoptosis in HCT116 cells. These results suggest that Calebin A can suppress multicellular TME-promoted CRC cell invasion and malignancy by inhibiting the NF-κB-promoting inflammatory pathway associated with carcinogenesis, underlining the potential of Calebin A for CRC treatment.

In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541...Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.