- |||||||||| pidnarulex (CX-5461) / Cylene, Senhwa Biosci
Journal: p53 activation during ribosome biogenesis regulates normal erythroid differentiation. (Pubmed Central) - Aug 22, 2020
Its premature arrest by the RNA Pol I inhibitor CX-5461 targeted the proliferation of immature erythroblasts...Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
- |||||||||| CX-5461 / Cylene
Journal: Cancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism. (Pubmed Central) - Aug 18, 2020
On the other hand, FANCJ knock-out cells expressing FeS cluster-deficient variants display a similar-enhanced-sensitivity towards pyridostatin (PDS) and CX-5461, two agents that stabilise G4 structures, as FANCJ knock-out cells. Mutations in FANCJ that abolish FeS cluster binding may hence be predictive of an increased cellular sensitivity towards G4-stabilising agents.
- |||||||||| cisplatin / Generic mfg., silmitasertib (CX-4945) / Senhwa Biosci, University of California
Journal: Emerging JWA-targeted Pt(IV) prodrugs conjugated with CX-4945 to overcome chemo-immune-resistance. (Pubmed Central) - Jul 29, 2020
Between them, Cx-platin-Cl augmented the infiltration and proliferation of T cells, alleviated the recruitment of T cells. The results provided compelling preclinical support that Cx-platin-Cl and Cx-DN604-Cl could reverse chemo-immune resistance via decaying JWA-XRCC1-mediated SSBR and immunosuppression, improving the development of emerging Pt(IV) candidate as a potential immunotherapeutic agent for cancer resistant prevention.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Review, Journal: Protein Kinase CK2 in Cancer Energetics. (Pubmed Central) - Jul 7, 2020
In fact, ATP-competitive inhibitors, synthetic peptides and antisense oligonucleotides have been designed as CK2 inhibitors, some of them used in preclinical models of cancer, of which TBB and silmitasertib are widely known. We will finish by discussing a hypothetical scenario in which cancer cells are "addicted" to CK2; i.e., in which many proteins that regulate signaling pathways and metabolism-linked processes are highly dependent on this kinase.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: Protein kinase CK2 is involved in zinc homeostasis in breast and prostate cancer cells. (Pubmed Central) - May 28, 2020
Knockdown of CK2β expression substantially increased the zinc level in breast cancer cell lines whilst decreased the zinc level in prostate cancer cells. Taken together, this study shows that CK2 is involved in zinc homeostasis of breast and prostate cancer cells and opens a new avenue for research on these cancers.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: New Dual CK2/HDAC1 Inhibitors with Nanomolar Inhibitory Activity against Both Enzymes. (Pubmed Central) - May 22, 2020
Remarkably, 15c showed 3.0 and 3.5 times higher inhibitory activity than the reference compounds CX-4945 (against CK2) and SAHA (against HDAC1), respectively. Compound 15c exhibited micromolar activity in cell-based cytotoxic assays against multiple cell lines.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Targeted combination treatment for B-cell acute lymphoblastic leukemia (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1773;
In conclusion, presented data show that CK2 and Ikaros regulate G1/S cell cycle progression via transcriptional regulation of the CCND3 gene in B-ALL and that CK2 inhibition represses CCND3 expression by enhancing Ikaros tumor suppressor function. Results demonstrate the synergistic efficacy of a combination treatment with CK2 inhibitor and dexamethasone and provide a rationale for the use of this combination treatment as a novel therapeutic approach for B-cell acute lymphoblastic leukemia.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
[VIRTUAL] CASEIN KINASE II INHIBITION SENSITIZES ACUTE LYMPHOBLASTIC LEUKEMIA CELLS TO VENETOCLAX VIA MCL-1 DEGRADATION () - May 16, 2020 - Abstract #EHA2020EHA_605;
Conclusion Our data indicates that inhibition of CK2 using the already clinically tested inhibitor CX is synergistic with the BCL-2 inhibitor VNT in ALL cells through destabilization of anti-apoptotic MCL-1. The strongest synergy was observed in samples with the lowest VNT sensitivity, providing a rationale to pursue this combination to circumvent VNT resistance in the clinical setting.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: The long-awaited structure of HIPK2. (Pubmed Central) - May 15, 2020
Agnew and colleagues present the first crystal structure of the HIPK2 kinase domain, complexed with the small-molecule inhibitor CX-4945, revealing important structural differences from related protein kinases of the DYRK family. This structure provides a starting point to exploit HIPK2's distinct structural features to develop selective small-molecule inhibitors of this kinase.
- |||||||||| CX-5461 / Cylene
Journal: CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage. (Pubmed Central) - May 15, 2020
This structure provides a starting point to exploit HIPK2's distinct structural features to develop selective small-molecule inhibitors of this kinase. This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Preclinical, Journal: Casein kinase 2 modulates the spindle assembly checkpoint to orchestrate porcine oocyte meiotic progression. (Pubmed Central) - Apr 16, 2020
Last, we found that the level DNA damage as assessed by γH2A.X staining was considerably elevated when CK2 was inhibited, suggesting that DNA damage might be another critical factor leading to the SAC activation and meiotic failure of oocytes. Our findings demonstrate that CK2 promotes the porcine oocyte maturation by ensuring normal spindle assembly and DNA damage repair.
- |||||||||| paclitaxel / Generic mfg.
Journal: Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer. (Pubmed Central) - Apr 15, 2020
In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. Conclusions These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California
Trial completion date, Trial primary completion date, Metastases: Treatment Duration Increment and Pharmacodynamic Study of CX-4945 in Patients With Basal Cell Carcinoma (BCC) (clinicaltrials.gov) - Apr 12, 2020
P1, N=26, Recruiting,
Conclusions These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC. Trial completion date: Mar 2021 --> Dec 2022 | Trial primary completion date: Mar 2020 --> Jun 2020
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells. (Pubmed Central) - Apr 10, 2020
Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target. (Pubmed Central) - Apr 10, 2020
Our findings uncover the oncogenic and poor prognostic roles of TET1 in EOC and suggest an unexplored role of epigenetic reprogramming in early ovarian carcinogenesis. Moreover, the immunomodulator CK2α represents a promising new therapeutic target, warranting clinical trials of the tolerable CK2 inhibitor, CX4945, for precision medicine against EOC.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region. (Pubmed Central) - Apr 10, 2020
Most significant structural differences between HIPK2 and DYRKs included an absence of the regulatory N-terminal domain, a unique conformation of the CMGC-insert region and of a newly defined insert segment in the aC-b4 loop. This first crystal structure of HIPK2 paves the way for characterizing the understudied members of the HIPK family and for developing HIPK2-directed therapies for managing cancer and fibrosis.
- |||||||||| quercetin (LY294002) / Eli Lilly, silmitasertib (CX-4945) / Senhwa Biosciences, University of California
Journal: Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells. (Pubmed Central) - Apr 10, 2020
However, we found that the PI3K inhibitor LY294002 reduced GSK3β pS9, and concomitantly decreased Snail1 levels (a GSK3β target and Epithelial-to-Mesenchymal transition marker). The effects of LY294002 were observed also in CK2β-downregulated cells, suggesting that reducing GSK3β pS9 could be a strategy to control Snail1 levels in any situation where CK2β is defective, as possibly occurring in cancer cells.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Trial primary completion date: A Phase I Study of CX5461 (clinicaltrials.gov) - Apr 9, 2020
P1, N=41, Active, not recruiting,
The effects of LY294002 were observed also in CK2β-downregulated cells, suggesting that reducing GSK3β pS9 could be a strategy to control Snail1 levels in any situation where CK2β is defective, as possibly occurring in cancer cells. Trial primary completion date: Apr 2020 --> Jul 2020
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences
Biomarker, Journal: An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancer. (Pubmed Central) - Apr 1, 2020
This approach is applicable to other oncogene driven cancers. FUND: This work was supported by grants from the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Lung Cancer Research Foundation and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosci, University of California, Verzenio (abemaciclib) / Eli Lilly, SNS-032 / Sunesis Pharma
Journal: Proteome and Phosphoproteome Changes Associated with Prognosis in Acute Myeloid Leukemia. (Pubmed Central) - Mar 21, 2020
This suggests that therapy against the upregulated kinases could also target the factors inducing their upregulation rather than their activity. This study, therefore, presents markers that could help predict AML relapse and direct therapeutic strategies.
- |||||||||| temozolomide / Generic mfg.
Journal: Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide. (Pubmed Central) - Feb 28, 2020
We found that loss of CK2 activity reduced β-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences
Journal: Structural Basis for the Selective Inhibition of Cdc2-Like Kinases by CX-4945. (Pubmed Central) - Feb 8, 2020
Thus, the relatively strong binding affinities of CX-4945 with CLK2 are consistent with its strong inhibitory effect defined in the previous study. These results may provide insights into structure-based drug discovery processes.
- |||||||||| silmitasertib (CX-4945) / Senhwa Biosciences
Journal: DNA‑PKcs inhibitor increases the sensitivity of gastric cancer cells to radiotherapy. (Pubmed Central) - Jan 27, 2020
The combination of NU7441 and CX4945 increased γH2AX expression in the nucleus of BGC823 cells following IR compared with treatment with NU7441 alone. Taken together, the findings suggest that DNA‑PKcs inhibitor increased the sensitivity of radioresistant BGC823 and MGC803 cells to radiotherapy through the cleaved‑caspase3/γH2AX signaling pathway, thus presenting a potential treatment method for GC.
- |||||||||| Lynparza (olaparib) / Merck (MSD), AstraZeneca
Activation of nucleolar DNA damage response as a therapeutic strategy for ovarian cancer (Trade Area Level 2&3) - Jan 24, 2020 - Abstract #LCC2020LCC_209;
P1
Our current focus includes: 1) understanding the mechanisms of CX-5461-induced DNA damage response (DDR) including how localized nucleolar DDR converts to a global DDR response; and 2) Understanding the mechanisms underlying the cooperation between CX-5461 and PARPi in inhibiting survival of HGSOC cells. This will provide evidence for the potential of this combination therapy against HGSOC and facilitate clinical trials to improve patients’ outcome.
- |||||||||| pidnarulex (CX-5461) / Senhwa Biosci
Trial completion date, Trial primary completion date: A Phase I Study of CX5461 (clinicaltrials.gov) - Jan 7, 2020
P1, N=41, Active, not recruiting,
Implications: This study identifies a new signaling pathway that contributes to enhancing cancer cell invasion. Trial completion date: Dec 2019 --> Dec 2020 | Trial primary completion date: Dec 2019 --> Apr 2020
- |||||||||| fluorouracil / Generic mfg.
Journal: Targeting the ribosome biogenesis key molecule fibrillarin to avoid chemoresistance. (Pubmed Central) - Dec 23, 2019
Targeting critical ribosome biogenesis components in order to decrease the genotoxic activity in cancer cell looks promising. Hence, we believe that targeting key protein rRNA methyltransferase FBL shows great potential, due to its pivotal role in ribosome biogenesis, its correlation to an improved survival rate at low expression in breast cancer patients and its association with p53.
- |||||||||| MK-2206 / Merck (MSD), miransertib (ARQ 092) / ArQule, silmitasertib (CX-4945) / Senhwa Biosciences
Review, Journal: CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways. (Pubmed Central) - Dec 21, 2019
These results suggest that AKT and CDK5 signaling contribute to the WM functional protection conferred by CK2 inhibition during ischemia, while inhibition of activated AKT signaling plays the primary role in post-ischemic protection conferred by CK2 inhibition in WM independent of age. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, our results will provide rationale for repurposing these drugs as therapeutic options for stroke patients by adding novel targets.
- |||||||||| CX-5461 / Cylene
Journal: A cell-based screening system for RNA polymerase I inhibitors. (Pubmed Central) - Dec 8, 2019
The model system was validated using the well-known RNA Pol I inhibitor CX-5461 by measuring transcribed human rRNA as readout...Preliminary studies demonstrated antiproliferative effects of cerivastatin sodium against human cancer cells, namely, A2780 and H460 cell lines. These results implicated cerivastatin sodium as a selective RNA Pol I inhibitor worthy of further development together with potential as a targeted anticancer therapeutic.
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