- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Loss of SETD2 disrupts ribosomal RNA transcription and processing to confer therapeutic vulnerabilities () - Nov 6, 2024 - Abstract #IKCS2024IKCS_98;
Alterations in ribosome biogenesis leads to epithelial-to-mesenchymal transition and metastasis in many tumor types, and our future goal will be to investigate the role of SETD2, ribosomes and rRNA transcription in transformation and metastasis in ccRCC.Figure: OOPS-proteomics identifies SETD2 as a regulator of ribosome biogenesis. RNA binding proteins are isolated from control or SETD2 -knockout cells identifies that metabolic proteins interact more with RNA (top right quadrant) while proteins regulating ribosome biogenesis (highlighted in orange)
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci
Targeted Therapy with CX4945 Biomimetic Nanodrug Delivery System for High-Risk B-Cell Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5207;
CX4945@PLGA-PEG@CM NPs is a biomimetic nanodrug with a core-shell structure, which has high stability and biocompatibility to delay the release of CX4945 drug and improve the bioavailability of the drug. Our study not only provides the evidence to get a better CK2 inhibitor for the therapy of B-ALL but also provides a theoretical basis using a biomimetic nano-delivery system to optimize drug treatment and even a new possibility for hematological drug research.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, pidnarulex (CX-5461) / Senhwa Biosci
Impaired rRNA Synthesis Contributes to BCL-2 Induced Chemoresistance in Diffuse Large B-Cell Lymphoma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4965;
In fact, combinations of RiBi inhibitors with drugs stabilizing p53 in a RiBi-independent manner, such as MDM2i or etoposide, restored efficient p53 stabilization in BCL-2 overexpressing DLBCL models...Furthermore, nucleolar area was an independent prognostic predictor in multivariate analysis, outperforming BCL-2 mRNA levels. These data indicate that the adverse prognostic influence related to BCL-2 overexpression could be due, in relevant part, to a reduced baseline rRNA synthesis rate, which in turn impairs p53-mediated response to chemotherapy, providing the rationale for novel, specific combination strategies aimed at overcoming BCL-2 induced chemoresistance in DLBCL.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci
CK2 FAVORS T-CELL CHEMOTAXIS THROUGHT THE RELEASE OF SOLUBLE FACTORS BY HODGKIN AND REED (Gro) - Oct 31, 2024 - Abstract #ISHL2024ISHL_73;
In this study, we assess the role of protein CK2 in sustaining T-cell recruitment in the tumor niche.HL cell lines (KM-H2 and HDLM-2) were treated with 0, 5, and 10 ?M of CX-4945 (CX), a CK2 inhibitor, for 24/48 h. Apoptosis was quantified by flow cytometry with the Annexin V/Propidium iodide assay...Among the tested cytokines, IL-6, M-CSF, RANTES, TARC, TGF-?1, TNF-?, and VEGF, demonstrated a significant CK2 dependence. When HL cell lines were treated with 10 ?M CX, there was a significant reduction of IL-6, TARC, TGF-?1, TNF-?, and VEGF release (p < 0.0001) and for some molecules also at 5 ?M.We also found that CM from HL cell lines was able to modulate the expression of the T-cell surface receptor CXCR3 but not CCR7, assessed by WB (p < 0.05), compared the untreated condition, which was not observed with the CM derived from CX-treated HL cells.In conclusion, CK2 emerged as a novel player in the formation of HL microenvironment by modulating the release of cytokines from HRS cells molecules that are able to chemoattract and shape chemokines receptor on the surface of T cells.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
ECT2-PLXNB2 Signaling Inhibits Ribosome Biogenesis Leading to Kidney Fibrosis (Exhibit Hall, Convention Center) - Sep 23, 2024 - Abstract #KIDNEYWEEK2024KIDNEY_WEEK_2367;
Collectively, our findings indicated that blocking RiBi initiated G2/M arrest and senescence of TECs as well as kidney fibrosis. ECT2 mediated PLXNB2 decline was a potential mechanism accounting for the impaired RiBi in fibrosis.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Preclinical, Journal: CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway. (Pubmed Central) - Sep 10, 2024
Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California, CIGB-300 / Center for Genetic Engineering and Biotechnology
Journal: "Phosphoproteomic quantification based on phosphopeptide intensity or occupancy? An evaluation based on casein kinase 2 downstream effects". (Pubmed Central) - Sep 8, 2024
A low overlap between the phosphoproteomes quantified by intensity and occupancy was obtained illustrating that new developments in proteomics techniques are needed to improve the performance of the occupancy approach. Even in such context, results indicate that occupancy quantification performs better than phosphorylation quantification based on intensity reinforcing the importance of such quantification approach to describe phosphoproteomic data.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Preclinical, Journal: Pharmacological inhibition of CK2 by silmitasertib mitigates sepsis-induced circulatory collapse, thus improving septic outcomes in mice. (Pubmed Central) - Aug 24, 2024
Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal, Metastases: Fibroblast growth receptor 1 is regulated by G-quadruplex in metastatic breast cancer. (Pubmed Central) - Aug 10, 2024
Importantly, use of the clinical G-quadruplex-stabilizing compound, CX-5461, stabilized the FGFR1 G-quadruplex structures, blocked the transcriptional activity of the FGFR1 proximal promoter, decreased FGFR1 expression, and resulted in potent inhibition of pulmonary tumor formation. Overall, our findings suggest G-quadruplex-targeted compounds could be a potential therapeutic strategy to limit the cellular plasticity of FGFR1 overexpressing MBC.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Enrollment open, Combination therapy: CX-4945 in Viral Community Acquired Pneumonia (clinicaltrials.gov) - Jul 31, 2024
P2, N=136, Recruiting,
Overall, our findings suggest G-quadruplex-targeted compounds could be a potential therapeutic strategy to limit the cellular plasticity of FGFR1 overexpressing MBC. Not yet recruiting --> Recruiting
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: CX-5461 Preferentially Induces Top2?-Dependent DNA Breaks at Ribosomal DNA Loci. (Pubmed Central) - Jul 27, 2024
poisons, we found that the Top2?-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.
- |||||||||| Mekinist (trametinib) / Novartis, BeiGene, silmitasertib (CX-4945) / Senhwa Biosci, University of California
(Phospho)Proteomic analysis reveals vulnerabilities in refractory metastatic colorectal cancer (Poster Exhibition; Spadolini Pavilion Ground Floor) - Jun 28, 2024 - Abstract #ECP2024ECP_1242;
Strikingly, the CKII inhibition combined with trametinib-mediated MEK blockade resulted in a synergistic interaction leading to enhanced antitumor activity. Conclusion Taken together, our findings propose the silmitasertib and trametinib combination as a new therapeutic opportunity for refractory mCRC patients and strengthen the use of PDO as a suitable model for drug screening.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: Alcohol exposure suppresses ribosome biogenesis and causes nucleolar stress in cranial neural crest cells. (Pubmed Central) - Jun 28, 2024
Similar results were obtained using a small molecule inhibitor of RNA Polymerase 1, CX5461, whereas p53-blocking morpholinos normalized craniofacial outcomes under high-dose alcohol...We conclude that alcohol causes the apoptosis of CNCs, at least in part, by suppressing ribosome biogenesis and invoking a nucleolar stress that initiates their p53-MDM2 mediated apoptosis. We further note that the facial deficits that typify PAE and some ribosomopathies share features including reduced philtrum, upper lip, and epicanthal distance, suggesting the facial deficits of PAE represent, in part, a ribosomopathy.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
A Splicing Modulator Inhibits Proliferation and Steroid Production of H295R Adrenocortical Cancer Cells (ENDOExpo PosterArea - BCEC) - May 5, 2024 - Abstract #ENDO2024ENDO_545;
The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: CK2 negatively regulates the extinction of remote fear memory. (Pubmed Central) - Apr 15, 2024
Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory...Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci, Farydak (panobinostat) / Secura Bio
Journal: Targeting the ribosome to treat multiple myeloma. (Pubmed Central) - Apr 10, 2024
In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk?MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Preclinical, Journal: Preclinical Targeting of the PGRMC1-CK2 Axis with Silmitasertib: A Potential Strategy for Lung Adenocarcinoma Therapy. (Pubmed Central) - Apr 10, 2024
Moreover, in-vitro colony formation assay, migration assay, and gene expression analysis using quantitative Real-time PCR revealed that Silmitasertib (IC50-2.5??M) was highly influential in suppressing the PGRMC1-CK2 expression axis. In conclusion, our study infers that PGRMC1-CK-2 axis inhibition could be a potential therapeutic option to limit the promotion and progression of lung cancer.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Casein kinase 2 phosphorylates and induces the SALL2 tumor suppressor degradation in colon cancer cells. (Pubmed Central) - Mar 21, 2024
Similarly, Sall2-deficient tumor organoids were more resistant to Silmitasertib-induced cell death, confirming that SALL2 sensitizes cancer cells to CK2 inhibition. We identified a novel CK2-dependent mechanism for SALL2 regulation and provided new insights into the interplay between these two proteins and their role in cell survival and proliferation.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia. (Pubmed Central) - Mar 12, 2024
Profiling of ERG- and c-MYC-dependent gene expression and analysis of ChIP-seq data established ERG and c-MYC coordinate a regulatory network in BCR::ABL1 B-ALL that controls expression of genes involved in several biological processes. Prominent was control of ribosome biogenesis, including expression of RNA polymerase I (POL I) subunits, the importance of which was validated by inhibition of BCR::ABL1 cells by POL I inhibitors, including CX-5461, that prevents promoter recruitment and transcription initiation by POL I. Our results reveal an essential ERG- and c-MYC-dependent transcriptional network involved in regulation of metabolic and ribosome biogenesis pathways in BCR::ABL1 B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Trial suspension, Surgery: Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery (clinicaltrials.gov) - Mar 11, 2024
P1/2, N=60, Suspended,
Prominent was control of ribosome biogenesis, including expression of RNA polymerase I (POL I) subunits, the importance of which was validated by inhibition of BCR::ABL1 cells by POL I inhibitors, including CX-5461, that prevents promoter recruitment and transcription initiation by POL I. Our results reveal an essential ERG- and c-MYC-dependent transcriptional network involved in regulation of metabolic and ribosome biogenesis pathways in BCR::ABL1 B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge. Recruiting --> Suspended
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
CK2 inhibiton exhibits synergistic effect in acute lymphoblastic leukemia (Section 43) - Mar 5, 2024 - Abstract #AACR2024AACR_6546;
The data shows that CK2 inhibitor, CX-4945, and c-KIT inhibitor, imatinib, exhibit a synergistic therapeutic effect. Imatinib is indicated for use in Philadelphia positive (Ph+) acute lymphoblastic leukemia so future studies will include testing CX-4945/imatinib synergy in Ph+ BALL where we expect to see more potent synergistic effect.
- |||||||||| Mekinist (trametinib) / Novartis, BeiGene, silmitasertib (CX-4945) / Senhwa Biosci, University of California
(Phospho)proteomic analysis reveals vulnerabilities in refractory metastatic colorectal cancer (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_5268;
We are currently integrating genomic and transcriptomic data to better characterize the observed drug synergy. Taken together, our findings propose the silmitasertib and trametinib combination as a new therapeutic opportunity for refractory mCRC patients and strengthen the use of PDO as a suitable model for drug screening.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci, Ibrance (palbociclib) / Pfizer, Avastin (bevacizumab) / Roche
Leveraging ChatGPT for literature-based inference of drug-gene relationships in cancer (Section 35) - Mar 5, 2024 - Abstract #AACR2024AACR_4847;
In summary, this pilot research serves as a foundational step towards the utilization of large language models in the field of drug discovery and development. Our ongoing efforts involve the rigorous evaluation of our approach across a diverse spectrum of drug targets and cancer types, as well as the optimization of prompts through state-of-the-art prompt engineering techniques.
- |||||||||| imatinib / Generic mfg.
Journal: CX?5461 potentiates imatinib?induced apoptosis in K562 cells by stimulating KIF1B expression. (Pubmed Central) - Feb 15, 2024
Moreover, using other leukemic cell lines, it was demonstrated that regulation of KIF1B expression by imatinib/CX-5461 was not a ubiquitous phenomenon in leukemic cells and should be studied in a cell type-specific manner. In conclusion, the results suggested that the synergistic interaction between CX-5461 and imatinib may be of potential clinical value for the treatment of tyrosine kinase inhibitor-resistant chronic myeloid leukemia.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: Genomic hallmarks and therapeutic targets of ribosome biogenesis in cancer. (Pubmed Central) - Feb 12, 2024
Moreover, we predicted 23 compounds, including methotrexate and CX-5461, associated with the expression signature of RiboSis genes. The current study generates a comprehensive blueprint of molecular alterations in RiboSis genes across cancers, which provides a valuable resource for RiboSis-based anti-tumor therapy.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Cancer selective cell death induction by a bivalent CK2 inhibitor targeting the ATP site and the allosteric ?D pocket. (Pubmed Central) - Feb 6, 2024
Using caspase activation assay, live-cell imaging, and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to representative ATP-competitive inhibitors, CX-4945, and SGC-CK2-1. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668, by targeting the CK2 ?D pocket, has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death in several cancer cell lines and stimulating distinct biological pathways in renal cell carcinoma.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Trial primary completion date, Surgery: Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery (clinicaltrials.gov) - Jan 26, 2024
P1/2, N=60, Recruiting,
Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668, by targeting the CK2 ?D pocket, has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death in several cancer cell lines and stimulating distinct biological pathways in renal cell carcinoma. Trial primary completion date: Sep 2028 --> Dec 2028
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal, BRCA Biomarker: The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells. (Pubmed Central) - Jan 15, 2024
It is under investigation in phase?I and II trials. Here, we find that, although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, nonselective, collateral mutagenesis in all three cell lines tested, to magnitudes that exceed known environmental carcinogens.
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