- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Trial completion date: A Phase I Study of CX5461 (clinicaltrials.gov) - Jun 14, 2022
P1, N=41, Active, not recruiting,
Identifying the developmental timing of periods of dysregulated DYRK1A may be important for understanding individual differences in neurodevelopmental trajectories in DS and for developing effective therapeutic interventions targeting DYRK1A. Trial completion date: Apr 2022 --> Dec 2022
- |||||||||| Biomarker, Journal: Integrated bioinformatics and statistical approaches to explore molecular biomarkers for breast cancer diagnosis, prognosis and therapies. (Pubmed Central) - Jun 4, 2022
Finally, we suggested KGs-guided computationally more effective seven candidate drugs (NVP-BHG712, Nilotinib, GSK2126458, YM201636, TG-02, CX-5461, AP-24534) compared to other published drugs by cross-validation with the state-of-the-art alternatives top-ranked independent receptor proteins. Thus, our findings might be played a vital role in breast cancer diagnosis, prognosis and therapies.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap, silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Mechanistic insights of key host proteins and potential repurposed inhibitors regulating SARS-CoV-2 pathway. (Pubmed Central) - May 31, 2022
Most of these drugs are in the preclinical phase, and some are already being used to treat severe COVID-19 patients. Hence, the mechanistic insight presented in this study is envisaged to support further findings of clinical studies and eventually develop efficient inhibitors to treat SARS-CoV-2.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Inhibition of CK2 Reduces NG2 Expression in Juvenile Angiofibroma. (Pubmed Central) - May 30, 2022
In addition, the loss of CK2 activity suppressed the JA cell proliferation and migration. These findings indicate that the inhibition of CK2 may represent a promising therapeutic approach for the treatment of NG2-expressing JA.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: DMPC/Chol liposomal copper CX5461 is therapeutically superior to a DSPC/Chol formulation. (Pubmed Central) - May 26, 2022
The reason for the improved activity of DMPC/Chol copper-CX5461 was not readily explained by the release data and may be due to the fact that DMPC/Chol liposomes are less stable following localization in the tumor. The results indicate that the therapeutic effects of copper-CX5461 will be dependent on liposomal lipid composition and that liposomal CX5461 should exhibit superior benefits when used to treat BRCA-deficient cancers.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: The therapeutic potential of RNA Polymerase I transcription inhibitor, CX-5461, in uterine leiomyosarcoma. (Pubmed Central) - May 18, 2022
The results indicate that the therapeutic effects of copper-CX5461 will be dependent on liposomal lipid composition and that liposomal CX5461 should exhibit superior benefits when used to treat BRCA-deficient cancers. SK-UT-1 was confirmed as a representative model of uterine leiomyosarcoma and CX-5461 has significant potential as a novel adjuvant for this rare cancer.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Trial completion date, Trial primary completion date: CX4945: Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19) (clinicaltrials.gov) - May 18, 2022
P2, N=40, Recruiting,
SK-UT-1 was confirmed as a representative model of uterine leiomyosarcoma and CX-5461 has significant potential as a novel adjuvant for this rare cancer. Trial completion date: Mar 2022 --> Jun 2022 | Trial primary completion date: Mar 2022 --> Jun 2022
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Transcriptional regulation of Rab21 GTPase in leukemia. (Pubmed Central) - May 14, 2022
Treatment of B-ALL cells with a specific CK2 inhibitors, CX-4945, resulted in increased Ikaros binding at the RAB21 promoter and reduced RAB21 expression...Together, these data demonstrate that Ikaros and CK2 regulate transcription and overall expression of RAB21 in B-cell ALL. Results uncovered an interplay between CK2 and Rab GTPase signaling pathways and suggest a mechanism by which CK2 regulates Rab21 activity in leukemia.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, silmitasertib (CX-4945) / Senhwa Biosci, University of California, Calquence (acalabrutinib) / AstraZeneca
INHIBITION OF PROTEIN KINASE CK2 AND BCL-2: A NOVEL THERAPEUTIC STRATEGY TO ANTAGONIZE MANTLE CELL LYMPHOMA CELL GROWTH () - May 13, 2022 - Abstract #EHA2022EHA_1711;
BCR inhibitors (Ibrutinib, Acalabrutinib) and antiapoptotic BCL2-family members blockers BH3-mimetics (Venetoclax, ABT-199) are effective drugs to fight MCL...The CK2 chemical inhibitor CX-4945 (Silmitasertib, Sil) is already under scrutiny in clinical trials in relapsed multiple myeloma, solid tumors and COVID-19...Remarkably, the calculated CI less than 1 suggested a strong synergic cell-killing effect between Sil and Ven, on all the cell lines tested, including those less sensitive or resistant to Ven Conclusion We demonstrated that the simultaneous inhibition/knock down of CK2 and BCL2 synergistically cooperates in inducing apoptosis and cell cycle arrest of MCL malignant B-lymphocytes and has the potential of reducing MCL clonal growth, also counterbalancing mechanism of resistance that may arise with Ven. Therefore, CK2 is a rational therapeutic target for the treatment of MCL to be tested in combination with Ibrutinib or Ven.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
OZM-114: Phase Ib expansion study of CX-5461in patients with solid tumors and BRCA2 and/or PALB2 mutation. (Available On Demand; 487a) - Apr 28, 2022 - Abstract #ASCO2022ASCO_5449;
P1
Secondary outcomes include evaluation of :1) Safety: CTCAE v 5.0, SAEs, dose modifications due to AEs, 2) Activity: best overall response from tumor evaluations performed every 2 cycles, according to RECIST v1.1, and duration of response., and 3) patient-reported outcomes: PRO (PRO-CTCAE v1.0 questionnaires to evaluate cutaneous, gastrointestinal, visual/perceptual, cardio/circulatory, sleep/wake and miscellaneous symptoms. Exploratory Objectives include assessment of: 1) anti-tumor activity of CX-5461 in patients with ovarian cancer and pathogenic/likely-pathogenic BRCA1 mutation and/or other HRD-associated somatic mutation, and 2) molecular profile of tumors and predictive value of mutational signatures in predicting response or resistance to CX-5461.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: Repression of T cell-mediated alloimmunity by CX-5461 via the p53-DUSP5 pathway. (Pubmed Central) - Apr 26, 2022
Mechanistically, CX-5461-induced immunosuppression was, at least partly, dependent on the p53-DUSP5 (dual-specificity phosphatase 5) axis and subsequent antagonism of the Erk1/2 mitogen-activated protein kinase pathway. In conclusion, our results suggest that CX-5461 is a promising candidate of a novel class of immunosuppressant which may be used as an alternative to the currently approved anti-rejection therapies.
- |||||||||| Review, Journal: Kinase Inhibitors as Potential Therapeutic Agents in the Treatment of COVID-19. (Pubmed Central) - Apr 22, 2022
The FDA approved baricitinib (a Janus kinase inhibitor) in combination with remdesivir for the treatment of COVID-19 patients receiving hospital care in November 2020. While in vitro trials with gilteritinib, fedratinib, and osimertinib are encouraging, further research is necessary before these inhibitors may be used to treat COVID-19 patients.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Direct MHC Class I Antigen Presentation Regulation by Ribosomal Biogenesis Inhibitor CX-5461 (Exhibit Hall; P107) - Apr 8, 2022 - Abstract #IMMUNOLOGY2022IMMUNOLOGY_1565;
Concurrently, presentation of the reporter peptide was diminished from both the DRiP and non-DRiP form of SCRAP. These data indicate that interruption of ribosome biogenesis has a minor impact on direct antigen presentation and protein synthesis.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Inhibition of Protein Kinase CK2 Affects Thymidylate Synthesis Cycle Enzyme Level and Distribution in Human Cancer Cells. (Pubmed Central) - Mar 15, 2022
Moreover, we show that CK2-mediated phosphorylation of TS enables the protein (pTS) interaction with SHMT1 and leads to the stability of the tri-complex containing SHMT1, DHFR, and pTS. Our results suggest an important regulatory role of CK2-mediated phosphorylation for inter- and intracellular protein level of enzymes involved in the thymidylate biosynthesis cycle.
- |||||||||| tamoxifen / Generic mfg.
Review, Journal: Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer. (Pubmed Central) - Mar 11, 2022
Using these chemicals might help reverse tamoxifen resistance in ER+ve breast cancer, provided that c-MYC-mediated ribosome biogenesis is the crucial factor for tamoxifen resistance. To employ these ribosome biogenesis inhibitors to combat tamoxifen resistance in the future, identification of predictive markers will be necessary.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Protein kinase CK2 is a potential therapeutic target in neuroblastoma (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_7738;
Targeting CK2 is a promising strategy with high potential to improve outcome in children with HR-NBL. CX-4945 shows a potent anti-tumor effect in NBL murine models.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Tumor treating fields induce DNA damage and apoptosis in medulloblastoma (Section 24) - Mar 9, 2022 - Abstract #AACR2022AACR_4043;
P1/2
In addition, combining CX-4945 and TTFields increased the number of cells with dysregulated actin which correlated with a decrease in MB migration and invasion. Our findings demonstrate that TTFields may be a novel and less toxic method to treat MB patients.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Review, Journal: Harnessing the Nucleolar DNA Damage Response in Cancer Therapy. (Pubmed Central) - Feb 10, 2022
We highlight the molecular consequences of rDNA damage including activation of the nucleolar DNA damage response, which is emerging as a unique response that can be exploited in anti-cancer therapy. In this review, we focus on CX-5461, a novel inhibitor of Pol I transcription that induces the nucleolar DNA damage response and is showing increasing promise in clinical investigations.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: p53 induces a survival transcriptional response after nucleolar stress. (Pubmed Central) - Feb 9, 2022
Using gene expression analysis, we find that p53 orchestrates a transcriptional program involved in promoting metabolic remodeling and autophagy to help cells survive under nucleolar stress. Importantly, our study demonstrates that blocking autophagy significantly sensitizes cancer cells to RNA Pol I inhibition by CX-5461, suggesting that interfering with autophagy should be considered a strategy to heighten the responsiveness of ribosome biogenesis-targeted therapies in p53-positive tumors.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: SGC-CK2-1 Is an Efficient Inducer of Insulin Production and Secretion in Pancreatic β-Cells. (Pubmed Central) - Jan 26, 2022
We used this compound in comparison with the well-established CK2 inhibitor CX-4945 to analyze the importance of CK2 for insulin production and secretion from pancreatic β-cells...Furthermore, both inhibitors increased the message for insulin and boosted the secretion of insulin from storage vesicles. Thus, regarding the high specificity of SGC-CK2-1, we can clearly attribute the observed effects to biological functions of protein kinase CK2.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Lead optimization, pharmacophore development and scaffold design of protein kinase CK2 inhibitors as potential COVID-19 therapeutics. (Pubmed Central) - Jan 12, 2022
CK2 inhibitors such as Silmitasertib have been proposed as possible therapeutic candidates in COVID-19 infections...These chemical features include; an anion, an aromatic ring and an H-bond acceptor. Based on the knowledge of these features; de-novo scaffold design was carried out which identified phenindiones, carboxylated steroids, macrocycles and peptides as novel scaffolds with the potential to modulate CK2.Communicated by Ramaswamy H. Sarma.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Activation of nucleolar DNA damage response as a therapeutic strategy for ovarian cancer () - Jan 7, 2022 - Abstract #LCC2022LCC_233;
Our current work utilises CRISPR-CAS9 screening approaches to characterise nucleolar DDR and how it mediates replication stress and to understand the mechanisms underlying CX-5461’s cooperation with PARPi in inhibiting the growth of HGSOC cells. This work will provide evidence for the potential of CX-5461 alone and in combination therapy approaches against HGSOC and for initiating clinical trials to improve patients’ outcomes.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Understanding and overcoming resistance to ribosome-targeting therapy in human acute myeloid leukaemia () - Jan 7, 2022 - Abstract #LCC2022LCC_68;
CX-5461 resistance was confirmed in vitro by measuring cell death/proliferation and cell cycle progression. The CX-5461 resistant MV4-11 cells lost the p53-mediated NSR and expression of p53 targets (e.g. p21) upon CX-5461 treatment, but CRISPR-mediated knockdown of p21 did not change CX-5461 sensitivity in MV4-11 cells.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Journal: The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma. (Pubmed Central) - Dec 29, 2021
CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity-often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.
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