- |||||||||| 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.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Trial completion date, Trial primary completion date: CX-5461-04: Study of CX-5461 in Patients With Solid Tumours and BRCA1/2, PALB2 or Homologous Recombination Deficiency (HRD) Mutation (clinicaltrials.gov) - Jan 3, 2024
P1, N=52, Recruiting,
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. Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Dec 2024
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Trial completion: A Study of Silmitasertib (CX-4945) in Healthy Subject (clinicaltrials.gov) - Dec 26, 2023
P1, N=30, Completed,
Learning Objectives: Understand applications of phosphoproteomic mass spectrometry in identifying signal dysregulation in cancer and discover pathways of interest. Active, not recruiting --> Completed
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum. (Pubmed Central) - Dec 2, 2023
Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete antimalarial mode of action of quarfloxin may be parasite-specific and remains somewhat elusive.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: 8-Chloroadenosine Induces ER Stress and Apoptotic Cell Death in Cholangiocarcinoma Cells. (Pubmed Central) - Nov 30, 2023
8-Chloroadenosine inhibited CCA cells by inducing endoplasmic reticulum stress and apoptosis. In vivo study showed that 8-CA inhibited cholangiocarcinoma tumor growth better when administered alone as compared to a combination with hydroxychloroquine.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California, tadalafil / Generic mfg.
Journal: Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors. (Pubmed Central) - Nov 27, 2023
Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Review, Journal: Boosting regulatory T cell-dependent immune tolerance by activation of p53. (Pubmed Central) - Nov 20, 2023
Evidence also suggests that pharmacological p53 activators may potentially be used to boost Treg-mediated immune tolerance. Based on these data, we argue that novel p53 activators such as CX-5461 may represent a distinct class of immunosuppressants that repress conventional T cell-mediated alloimmunity with concomitant boosting of Treg-dependent immune tolerance.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Targeting fibroblast growth factor receptor (FGFR1) expression through G-quadruplex stabilization inhibits metastatic breast cancer (Hall 2-3) - Nov 4, 2023 - Abstract #SABCS2023SABCS_940;
Importantly, use of the G4-binding compound CX-5461 stabilized the FGFR1 G4 structure, blocked the transcriptional activity of the FGFR1 proximal promoter and decreased FGFR1 expression...In conclusion, consistent with the clinical observations our evaluation of FGFR kinase inhibitors validates the resistance to FGFR kinase inhibitors in MBC. Our findings indicate that targeting FGFR1 expression through G4 stabilization may be a potential strategy for MBC.
- |||||||||| OICR-9429 / FACIT, silmitasertib (CX-4945) / Senhwa Biosci, University of California
Dual Targeting Novel WDR5/ATAD2 Oncogenic Signaling through CK2/Ikaros Axis Demonstrates Synergistic Efficacy in T-ALL (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5618;
Our study reveals a model that dual targeting WDR5/ATAD2 signaling through direct inhibiting oncoproteins and via CK2/IKAROS axis to transcriptionally repress the oncoprotein to achieve synergistic efficacy. Our results further highlight the combination of CX-4945 with WDR5 inhibition is a potential option for the therapy of T-ALL patients.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California, Xpovio (selinexor) / Karyopharm, Menarini, FORUS Therap
Selinexor Synergizes CX4945 on Anti-Tumor Effect By Targeting XPO1/Ikros/c-Myc Signaling in T-Cell Acute Lymphoblastic Leukemia (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_3934;
Conclusions The combination of Selinexor and CX4945 has synergistic effects on cell proliferation arrest and apoptosis in T-ALL by targeting the XPO1/IKROS/c-Myc signaling. Our results also provide experimental evidence for the new combination of Selinexor and CX4945 as a new potential therapeutic option for T-ALL patients.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Purine Metabolism Modulates Leukemia Stem Cell Maintenance in MLL-Rearranged Acute Leukemia (Marriott Marquis - Marriott Grand) - Nov 3, 2023 - Abstract #ASH2023ASH_3258;
We utilized genetic and pharmacological (mycophenolate mofetil, MMF, a purine biosynthesis inhibitor of IMPDH) approaches to target the enhanced purine metabolism and found inhibition of the purine synthesis pathway promotes myeloid differentiation of both murine and human LSCs...Moreover, we found that the myeloid differentiation induced by MMF or CX-5461 is associated with reduced chromatin occupancy of the MLL-AF9 complex, especially Menin, and downregulated expression of MLL-AF9 target genes, such as Meis1, Hoxa9, and Myc , suggesting a regulatory role of nucleolar rRNA transcription on MLL-AF9 oncogenic gene expression program...Altogether, our findings reveal that purine metabolism maintains nucleolar rRNA transcription homeostasis to modulate MLL fusion complex-induced leukemogenic transcriptional activity in LSCs. The enhanced purine metabolism emerges as a crucial dependency for LSCs, providing potential targets for novel therapeutic strategies in treating MLL-rearranged leukemia.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Trial termination, Metastases: A Phase 1, Open-Label, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered CX-5461 in Patients with Advanced Haematologic Malignancies (EUDRACT) - Nov 2, 2023
P1, N=40, Terminated,
The enhanced purine metabolism emerges as a crucial dependency for LSCs, providing potential targets for novel therapeutic strategies in treating MLL-rearranged leukemia. Recruiting --> Terminated
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress. (Pubmed Central) - Oct 22, 2023
We found that CX-5461, an RNPI inhibitor, recapitulated the effect of Spen ablation on tumor vessel normalization, and combining CX-5461 with cisplatin substantially improved the efficacy on treating tumors in mice. Together, these results demonstrate that SPEN is required for angiogenesis by repressing pRNA to enable rRNA gene transcription and ribosomal biogenesis, and that RNPI represents a target for tumor vessel normalization therapy of cancer.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Trial termination: CX4945: Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19) (clinicaltrials.gov) - Aug 14, 2023
P2, N=31, Terminated,
accelerates skin wound healing in T1D mice by promoting endothelial cell proliferation via the Hedgehog signaling pathway. Completed --> Terminated; After 15 months of active enrollment and a lack of qualifying hospitalized COVID-19 patients, the Sponsor-Investigator, Marilyn Csete Glassberg, MD, decided to terminate recruitment before meeting the stated enrollment objectives.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Review, Journal: Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia. (Pubmed Central) - Jul 29, 2023
Several CK2 inhibitors have been developed, but CX-4945/silmitasertib is best characterized...However, clinical AML studies are not available. Taken together, the available experimental and clinical evidence suggests that the possible use of CK2 inhibition in the treatment of AML should be further investigated.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: Small Molecule RBI2 Disrupts Ribosome Biogenesis through Pre-rRNA Depletion. (Pubmed Central) - Jul 14, 2023
Next-generation RNA sequencing (RNA-seq) revealed that RBI2 and previously described ribosome biogenesis inhibitor CX-5461 induce distinct changes in the transcriptome...Northern blotting revealed that RBI2 does not appear to impair or alter rRNA processing. Collectively, these data suggest that RBI2 inhibits rRNA synthesis differently from other previously described ribosome biogenesis inhibitors, potentially acting through a novel pathway that upregulates the turnover of premature rRNAs.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal, Synthetic lethality: A Synthetic Lethal Approach to Drug Targeting of G-Quadruplexes Based on CX-5461. (Pubmed Central) - Jul 3, 2023
Screening results confirmed the synthetic lethal interaction between G4 stabilizers and HR genes and also uncovered other novel genetic interactions, including genes in other DNA damage repair pathways and genes in transcription, epigenetic, and RNA processing deficiencies. In addition to patient identification, synthetic lethality is also important for the design of drug combination therapy for G4-targeting drugs in order to achieve better clinical outcomes.
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