- |||||||||| cisplatin / Generic mfg.
Journal: CSNK2A1-mediated phosphorylation of HMGA2 modulates cisplatin resistance in cervical cancer. (Pubmed Central) - Jun 12, 2021
CX-4945, a CSNK2A1 inhibitor, could inhibit the phosphorylation of HMGA2 and sensitize tumor cells to cisplatin. Our results reveal that CSNK2A1-dependent HMGA2 phosphorylation may partially underlie cisplatin-resistance in cervical cancer, suggesting that HMGA2 phosphorylation may have potential as a predicative biomarker and therapeutic target to improve chemotherapeutic efficacy.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor. (Pubmed Central) - May 27, 2021
However, the polar carboxylic acid moiety that is shared by many CK2 inhibitors including silmitasertib was required for potency but limits the cellular activity of IC20 (31) and the cellular IC dropped to the low micromolar range. In summary, IC20 (31) represents a highly selective and potent inhibitor of CK2, which can be used as a tool compound to study CK2 biology and potential new applications for the treatment of diseases.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Clinical, Journal: Flavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy. (Pubmed Central) - May 15, 2021
Several potent and relatively specific inhibitors of CK2 are now being evaluated as potential cancer drugs; CX-4945 has shown impressive activity in cell culture studies and xenograft models, and is now entering clinical trials...Enzymatically modified isoquercitrin has particular promise as a delivery vehicle for quercetin. Hence, it may be worthwhile to explore the clinical potential of flavones/flavonols as CK2 inhibitors for cancer therapy.
- |||||||||| Zarzio (filgrastim biosimilar) / Novartis
[VIRTUAL] ROLE OF PROTEIN KINASES CK1 ALPHA AND CK2 IN CHRONIC ACTIVE BCR-DEPENDENT SIGNALING NETWORK IN MANTLE CELL LYMPHOMA: EFFECTS ON BTK-DIRECTED THERAPY. () - May 13, 2021 - Abstract #EHA2021EHA_1545;
New drugs targeting the B Cell Receptor (BCR) dependent signaling pathways, such as ibrutinib, acalabrutinib, zanubrutinb and other BTK inhibitors, have been proved therapeutically efficient in MCL, but the disease remains uncurable...CK1 or CK2 chemical inhibition with D4476 or CX-4945 respectively, caused, a reduction in the activating phosphorylation of S536 p65/RelA and S473 AKT, important signaling events downstream the BCR...Our data also indicate that these kinases could antagonize ibrutinib -induced apoptosis. Therefore, CK1α and CK2 could be rational therapeutic targets for the treatment of MCL, particularly those aggressive, ibrutinib-resistant forms.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Protein kinase CK2 inhibition as a pharmacological strategy. (Pubmed Central) - May 6, 2021
However, CK2 activity has been found instrumental in many other human pathologies, and its inhibition will expectably be extended to different purposes in the near future. Here, after a description of CK2 features and implications in diseases, we analyze the different inhibitors and strategies available to target CK2, and update the results so far obtained by their in vivo application.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Clinical, Journal: Comparing the efficacy and selectivity of Ck2 inhibitors. A phosphoproteomics approach. (Pubmed Central) - May 1, 2021
To sum up, we can conclude that by treating C2C12 cells for 5 h with either CX4945 or GO289 off-target effects are negligible since almost all the phosphosites undergoing a substantial reduction are attributable to CK2, with a higher inhibitory efficacy displayed by GO289. CX4945 and GO289 provide highly selective tools to control the CK2-dependent phosphoproteome compared with previously developed CK2 inhibitors.
- |||||||||| pidnarulex (CX-5461) / Cylene, Senhwa Biosci
Journal: The Wnt/β-Catenin pathway is activated as a novel nucleolar stress response. (Pubmed Central) - Apr 27, 2021
Moreover, triggering nucleolar stress by the chemotherapeutic agents ActinomycinD or the RNA polymeraseI inhibitor CX-5461 stimulates expression of Wnt/β-Catenin targets, which is followed by the p53 target CDKN1A(p21). As PPAN expression is induced by Wnt/β-Catenin signaling, our data establish a novel feedback mechanism and reveal that nucleolar stress over-activates the Wnt/β-Catenin pathway, which most likely serves as compensatory mechanism to sustain ribosome biogenesis.
- |||||||||| 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) - Apr 22, 2021
P2, N=40, Recruiting,
As PPAN expression is induced by Wnt/β-Catenin signaling, our data establish a novel feedback mechanism and reveal that nucleolar stress over-activates the Wnt/β-Catenin pathway, which most likely serves as compensatory mechanism to sustain ribosome biogenesis. Trial completion date: Mar 2021 --> Sep 2021 | Trial primary completion date: Mar 2021 --> Sep 2021
- |||||||||| pidnarulex (CX-5461) / Cylene, Senhwa Biosci
Journal: Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis. (Pubmed Central) - Apr 20, 2021
Our previous first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single-agent efficacy in refractory blood cancers...Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Clinical, PK/PD data, Journal: LC-MS/MS method for quantitation of the CK2 inhibitor silmitasertib (CX-4945) in human plasma, CSF, and brain tissue, and application to a clinical pharmacokinetic study in children with brain tumors. (Pubmed Central) - Apr 13, 2021
This assay was also validated for each matrix for selectivity, sensitivity, matrix effects, recovery, and stability. We applied the validated method to the analysis of plasma silmitasertib for a clinical study.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Preclinical, Journal: Mechanistic Basis for In Vivo Therapeutic Efficacy of CK2 Inhibitor CX-4945 in Acute Myeloid Leukemia. (Pubmed Central) - Apr 7, 2021
Overall, these results establish the in vivo therapeutic efficacy of CX-4945 in AML preclinical models and determine the role of CK2 and IKAROS in regulating apoptosis in AML. Furthermore, our study provides functional and mechanistic bases for the addition of CK2 inhibitors to AML therapy.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes. (Pubmed Central) - Apr 1, 2021
Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes...These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
[VIRTUAL] Tumor treating fields induce DNA damage and apoptosis in medulloblastoma () - Mar 11, 2021 - Abstract #AACR2021AACR_1447;
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.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: A N-terminally deleted form of the CK2α' catalytic subunit is sufficient to support cell viability. (Pubmed Central) - Mar 11, 2021
This mutant sheds light on the role of the CK2 N-terminal segment as a regulator of activity and stability. Comparable cytotoxic efficacy of two selective and structurally unrelated CK2 inhibitors support the view that survival of CK2α/α' cells relies on this deleted form of CK2α', whose discovery provides novel perspectives about the biological role of CK2.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci
Trial completion date, Trial primary completion date: Evaluating Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in Subjects With Moderate COVID-19 (clinicaltrials.gov) - Mar 4, 2021
P2, N=20, Recruiting,
Comparable cytotoxic efficacy of two selective and structurally unrelated CK2 inhibitors support the view that survival of CK2α/α' cells relies on this deleted form of CK2α', whose discovery provides novel perspectives about the biological role of CK2. Trial completion date: Mar 2021 --> Jun 2021 | Trial primary completion date: Feb 2021 --> May 2021
- |||||||||| pidnarulex (CX-5461) / Cylene, Senhwa Biosci, sapanisertib (TAK-228) / Takeda
Journal: Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma. (Pubmed Central) - Feb 25, 2021
Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Regulation of TMEM16A by CK2 and Its Role in Cellular Proliferation. (Pubmed Central) - Feb 24, 2021
Simultaneous inhibition of TMEM16A by niclosamide and inhibition of CK2 by silmitasertib was additive with respect to blocking cell proliferation, while cytotoxicity was reduced when compared to solely blockade of CK2. Therefore, parallel blockade TMEM16A by niclosamide may assist with anticancer therapy by silmitasertib.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Protein Kinase CK2 Controls Ca2.1-Dependent Calcium Currents and Insulin Release in Pancreatic β-Cells. (Pubmed Central) - Feb 23, 2021
Ca2.1 knockdown experiments showed that the increase in the intracellular Ca concentration, followed by an enhanced insulin secretion upon CK2 inhibition, is due to a Ca influx through Ca2.1 channels. In summary, our results point to a modulating role of CK2 in the Ca2.1-mediated exocytosis of insulin.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Trial completion date: A Phase I Study of CX5461 (clinicaltrials.gov) - Feb 18, 2021
P1, N=41, Active, not recruiting,
In summary, our results point to a modulating role of CK2 in the Ca2.1-mediated exocytosis of insulin. Trial completion date: Dec 2020 --> Jun 2021
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Protein kinase CK2 impact on intracellular calcium homeostasis in prostate cancer. (Pubmed Central) - Feb 13, 2021
PCa cells were treated with the CK2 small molecule inhibitors 4,5,6,7-tetrabrombenzotriazole and CX-4945 followed by analysis of Ca levels in various cellular compartments over time...In cells with death-inducing levels of CK2 inhibition, total cellular Ca levels dropped at 2 h post-treatment. These novel observations represent a potential mechanism underlying regulation of cell survival and death by CK2 activity.
- |||||||||| Mekinist (trametinib) / Novartis, silmitasertib (CX-4945) / Senhwa Biosci, University of California
[VIRTUAL] CK2 inhibition synergizes with MAPK inhibition to overcome resistance in acral melanoma () - Feb 12, 2021 - Abstract #SID2021SID_568;
To translate these findings, we treated NF1-null human melanoma cells grown as xenografts in nude mice with CX4945, and noted a significant reduction in tumor growth that resulted in stable disease. Together, our results suggest that the combination of CK2 inhibitors with MEK inhibitors, and potentially other tyrosine kinase inhibitors, may improve therapeutic outcomes in difficult to treat malignant melanomas of acral origin.
- |||||||||| CX-5461 / Cylene
Review, Journal: Targeting the RNA Polymerase I Transcription for Cancer Therapy Comes of Age. (Pubmed Central) - Feb 12, 2021
The realization that the increase in rRNA expression has an active role in cancer progression, not only through increased protein synthesis and thus proliferative capacity but also through control of cellular check points and chromatin structure, has opened up new therapeutic avenues for the treatment of cancer through direct targeting of Pol I transcription. In this review, we discuss the rational of targeting Pol I transcription for the treatment of cancer; review the current cancer therapeutics that target Pol I transcription and discuss the development of novel Pol I-specific inhibitors, their therapeutic potential, challenges and future prospects.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells. (Pubmed Central) - Feb 3, 2021
Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1c ) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib...These findings suggest that CK2-dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC-like traits. Therefore, phospho-ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Review, Journal: Cellular signaling and epigenetic regulation of gene expression in leukemia. (Pubmed Central) - Jan 28, 2021
Treatment of leukemia cells with a specific inhibitor of CK2 restores Ikaros function, resulting in cytotoxicity of leukemia cells. Here, we review the mechanisms through which the CK2-Ikaros signaling axis regulates the global epigenomic landscape and expression of genes that control cellular proliferation in leukemia.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Enrollment open, Trial completion date, Trial primary completion date: CX4945: Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19) (clinicaltrials.gov) - Jan 21, 2021
P2, N=40, Recruiting,
Here, we review the mechanisms through which the CK2-Ikaros signaling axis regulates the global epigenomic landscape and expression of genes that control cellular proliferation in leukemia. Not yet recruiting --> Recruiting | Trial completion date: Dec 2022 --> Mar 2021 | Trial primary completion date: Dec 2022 --> Mar 2021
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Clinical, Journal: "JANUS" EFFICACY OF CX-5011: CK2 INHIBITION AND METHUOSIS INDUCTION BY INDEPENDENT MECHANISMS. (Pubmed Central) - Jan 8, 2021
Small molecules, such as indole-based calchones, have been identified as methuosis inducers and, recently, the CK2 inhibitor CX-4945 has been shown to have a similar effect on different cell types...Worthy of note, CX-5011 is able to promote macropinocytosis not only in mammalian cells, but also in an in-vivo zebrafish model. Based on these evidences, CX-5011 is, therefore, proposed as a potential promising compound for cancer therapies for its dual efficacy as an inhibitor of the pro-survival kinase CK2 and inducer of methuosis.
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