silmitasertib (CX-4945)

Our findings suggest an important role of ECE-1c in lung cancer. ECE-1c is key in a non-canonical ET-1-independent mechanism which triggers a CSC-like phenotype, leading to enhanced lung cancer aggressiveness. Underlying this mechanism, ECE-1c is stabilized upon phosphorylation by CK2, which is upregulated in many cancers. Thus, phospho-ECE-1c may be considered as a novel prognostic biomarker of recurrence, as well as the CK2 inhibitor silmitasertib as a potential therapy for lung cancer patients.

P1/2, N=114, Recruiting, Milton S. Hershey Medical Center | Not yet recruiting --> Recruiting

Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

P1/2, N=114, Not yet recruiting, Milton S. Hershey Medical Center

P2, N=136, Recruiting, Senhwa Biosciences, Inc. | Not yet recruiting --> Recruiting

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2β subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa.

Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin. The skewed expression between CK2α and CK2β has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.

Several drugs, such as lapatinib, silmitasertib, itraconazole, and dasatinib, were sensitive to DHODH expression and exhibited strong molecular binding with it. Thus, DHODH may promote ccRCC progression and is a candidate effective therapeutic target for ccRCC.

Macropinocytosis is used as an energy source in the KRAS mutant CCA cell line HuCCT1. The inhibition of CK2 by CX-4945 leads to cell death in HuCCT1 cells through alteration of the lysosome-dependent metabolism.

P1/2, N=60, Suspended, Pediatric Brain Tumor Consortium | Recruiting --> Suspended

P1/2, N=60, Recruiting, Pediatric Brain Tumor Consortium | Trial primary completion date: Sep 2028 --> Dec 2028

P1/2, N=60, Recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Nov 2028 --> Feb 2029

P2, N=136, Not yet recruiting, Senhwa Biosciences, Inc.

P1, N=30, Completed, Senhwa Biosciences, Inc. | Active, not recruiting --> Completed

Currently available therapeutic approaches for Mantle Cell Lymphoma (MCL), including the Bruton Tyrosine Kinase (BTK) inhibitors ibrutinib, acalabrutinib and zanubrutinib, are not curative...In MCL, BET inhibitors, such as INCB054329 or JQ-1, have been shown to increase apoptosis through downregulation of the AKT-mTOR, ERK, and other B Cell Receptor (BCR)-triggered cascades...The most effective and tested CSNK2 chemical inhibitor is CX4945 (silmitasertib), but very recently a novel compound, SGC-CK2, has been developed...Remarkably, CK2 inactivation led to a robust reduction of the BET inhibitor-induced increase of Mcl1, and NF-kB Ser 529 phosphorylation, thus counteracting BET-inhibitors-evoked compensatory pathways that could favor apoptosis resistance. Therefore, combined CSNK2 and BET proteins inhibition could represent an innovative strategy for chemotherapy and BTKi-resistant MCL.

Moreover, about 80% of Ph +B-ALL patients have the IKZF1 deletion, our ChIP-seq data showed that IKZF1-encoded Ikaros protein binds to the promoter region of PTPN11 and CK2 inhibitor CX4945 as Ikaros function activator dramatically increase the Ikaros binding to the promoter of PTPN11 in B-ALL cells and Ikaros directly suppresses its promoter activity (Fig. Conclusions The combination of AZA and FLU has a synergistic anti-leukemia effect on cell proliferation arrest and apoptosis in Ph +ALL cells with IKZF1-deletion by targeting Ikaros/PTPN11/Ras oncogenic signaling. Our data provide experimental evidence for a new potential combination of AZA with FLU in the therapy of Ph +ALL and highlight the likelihood of the novel combination in ALL patients.

Our report suggests that the inhibitory effects of CX4945 on MMP-1 in epidermal cells may offer a basis for further studying its therapeutic potential as an anti-wrinkle agent.

Background: Resistance to endocrine therapy (ET; tamoxifen, aromatase inhibitors, AI, or fulvestrant) in ER+ breast cancer (BC) could be due to survival of breast cancer stem cells (BCSCs)...We discovered a novel and potent anti-BCSC gene, Death Associated Protein 6 (DAXX) through a pre-surgical biomarker window study combining ET plus a Notch inhibitor [MK-0752, a g-secretase inhibitor (GSI)]...ER+ cells were treated with kinase inhibitors for AURKA (alisertib), AURKB (barasertib), CK1 (CK-IN-1), or CK2 (CX-4945) and DAXX protein was detected by western blotting... ET decreased DAXX protein levels in ER+ PDX and human tumors. Downregulation of the DAXX protein by ET was through activation of AURKB and hyper-phosphorylation of DAXX which resulted in protein degradation and enhanced survival of BCSCs. Therefore, Inhibition of AURKB using barasertib partially restored DAXX expression, inhibited BCSCs, and delayed tumor recurrence.

RNA-seq was performed after CEM cells were treated with WDR5 inhibitor (OICR-9429), CX-4945 and vehicle control for 72 hours. 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.

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.

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.

C-MYC-MAX and β-catenin-MAX binding to E-box site or β-catenin-MAX bound to TCFs/LEF1 enhanced HMGB1 or IL-6 promoter activities, respectively. IL-6 and HMGB1 secreted by hepatocytes, HSCs, and KCs exert paracrine effects on cholangiocytes to promote cell growth, migration, and invasion and lead to the progression of cholangiocarcinogenesis. CX-4945 provides perspectives on therapeutic strategies to attenuate progression from atypical cystic hyperplasia to cholangiocarcinogenesis.

Glioblastoma cells were engineered to express these SGT vectors and used to evaluate the CK2-dependent stabilization of the novel HSVtk fusions in response to the CK2 inhibitor CX-4945. Further, we demonstrated the ability of this SGT to induce cell death upon administration of the prodrug ganciclovir. In addition to generating a novel CK2-regulated SGT, this work develops a platform for the rational engineering of other oncogenic kinase-stabilized SGTs.

Our data demonstrated for the first time the synergistic effect of a novel combination of KPT-330 and CX-4945 on cell growth arrest and apoptosis in AML cells, and identify the underlying mechanism bytargeting the PIK3CD/AKT1/FOXO3 signaling pathway, which highlighted the feasibility of clinical trials for combination therapy of AML patients.

In the present work, we established six novel imatinib- and dasatinib-resistant CML cell lines, all of which had increased CK2 activation. A CK2 inhibitor, CX-4945, induced cell death of CML cells in both parental and resistant cell lines...No effects of CK2 inhibition were observed in normal mononuclear blood cells from healthy donors and BCR-ABL negative HL60 cell line. Our data indicate that CK2 kinase supports CML cell viability even in cells with different mechanisms of resistance to TKI, and thus represents a potential target for treatment.

CX- 4945, a selective inhibitor of CK2, induces cell cycle arrest and cell death in cholangiocarcinoma cells via the regulation of PLK1 and p53. This may provide a novel therapeutic strategy for advanced cholangiocarcinoma.

The degradation of 16E2 promotes HPV16 genome integration; therefore, the E2-TopBP1 interaction is critical during the viral life cycle. We demonstrate that the CK2 inhibitor CX4945 disrupts HPV11 interaction with TopBP1 and destabilizes HPV11 E2 protein in the presence of J2 fibroblasts; we propose that CX4945 could alleviate HPV11 disease burden.

P1, N=25, Active, not recruiting, Senhwa Biosciences, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Sep 2022 --> Sep 2023

Thus, the interplay between CK2 and PP1 signaling pathways have opposing effects on the phosphorylation status of their mutual substrate - IKAROS. This review summarizes the effects of CK2 and PP1 on IKAROS role in regulation of gene expression and its function as a tumor suppressor in leukemia.

Combinations of the multitarget drug trabectedin with either the CK2/CLK double-inhibitor CX-4945 (silmitasertib) or the c-MET/TAM (TYRO3, Axl, MERTK) receptor inhibitors foretinib and cabozantinib demonstrated synergistic effects and induced apoptosis (relative caspase 3 and 7 activity increased up to 20.5-fold in UM cell lines)...Trabectedin alone or in combination with cabozantinib inhibited tumor growth in PDX UM mouse models. Blocking of MERTK, rather than TYRO3, activity inhibited UM cell growth and synergized with trabectedin.

Silmitasertib and bortezomib were used as CK2a and proteasome inhibitors. We demonstrated that CK2a is overexpressed active induced key pro-survival signals in HL and its inhibition trigger apoptosis. CK2b is likely downregulated due to proteasome degradation. These preliminary data suggest that CK2 might be a new therapeutic target in HL.

Targeting of CK2, either by inducible short hairpin RNA (shRNA)-mediated knockdown of CK2 or by the CK2-inhibitor silmitasertib, did not affect cell viability by itself, but strongly synergized with venetoclax, also if combined with ibrutinib, in both MCL cell lines and primary samples. Taken together, our findings indicate that targeting of CK2 sensitizes MCL cells to venetoclax through downregulation of MCL-1. These novel insights provide a strong rationale for combining venetoclax with CK2 inhibition as therapeutic strategy for MCL patients.

The findings of this study demonstrate that TTFields may be a novel and less toxic method to treat patients with MB.

CX-4945 synergizes the antitumor activity of YAP-TEAD inhibitors verteporfin and Super-TDU. Elevated expression of HHEX is correlated with hyperactivation of YAP/TEAD and associated with poor prognosis of CRC patients. Overall, our study identifies HHEX as a positive modulator of YAP/TEAD to promote colorectal tumorigenesis, providing a new therapeutic strategy for targeting YAP/TEAD in CRC.

Consistently, low CDCA3 expression (H-score 0.001)...CK2 blockade to upregulate CDCA3, especially prior to development of therapy resistance and in CDCA3 low settings, might benefit people living with EGFR mutant NSCLC by improving the response to EGFR TKIs. Given our published work demonstrating CDCA3 as a biomarker for platinum-based chemotherapy response in NSCLC without EGFR mutations, our biomarker may also have utility to enhance the effectiveness of chemoimmunotherapy in EGFR mutant tumors.

CX-4945 induces cell cycle arrest and cell death in cholangiocarcinoma cells via the regulation of PLK1 and p53. This may provide a novel therapeutic strategy for advanced cholangiocarcinoma.

Furthermore, there was a time-differential negative regulation of HIF-1α expression by CX-4945 in HuCCT-1 cells, and knockdown of HIF-1α caused a significant reduction of the cell survival. In summary, these results demonstrated that CX-4945 has anti-growth, anti-angiogenic, and pro-apoptotic effects on HuCCT-1 cells, which are mediated through control of CK2, caspase-9/3, DR-4, STAT-3/5, Mcl-1, eIF-2α, and HIF-1α.