silmitasertib (CX-4945) / Senhwa Biosci, Cylene - LARVOL DELTA

REPURPOSING AN ANTICANCER AGENT FOR THE TREATMENT OF HUNTINGTON'S DISEASE (ADPD 2025) - "These results establish CX4945 as a promising therapeutic agent for HD and reveal novel regulatory mechanisms of astrocytes in HD."

CNS Disorders • Huntington's Disease • Movement Disorders • Oncology

Assessment of repurposed compounds against coronaviruses highlights the antiviral broad-spectrum activity of host-targeting iminosugars and confirms the activity of potent directly acting antivirals. (PubMed, Antiviral Res) - "We observed 13 compounds showing antiviral activity against SARS-CoV-2, including seven FDA-approved compounds (remdesivir, boceprevir, amiloride, nafamostat, cisplatin, silmitasertib, and miglustat), and six compounds in pre-clinical and clinical development (tarloxotinib, lucerastat (NB-DGJ), MON-DNJ, NAP-DNJ, NN-DGJ and NN-DNJ). Its activity also extended to another betacoronavirus HCoV OC43, but not alphacoronavirus HCoV 229E. Our cellular screening results add to the body of knowledge on antivirals against coronaviruses and confirm the antiviral efficacy of iminosugars in cellular assays using the human lung-cell line Calu-3."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Single-cell and spatial transcriptomics reveal pre-metastatic subsets and therapeutic targets in penile carcinoma. (PubMed, iScience) - "Silmitasertib, a CK2α inhibitor, exhibited anti-tumor effects in penile carcinoma cells. Validated across 98 single-cell and 6 spatial datasets, our study advances the understanding of tumorigenesis and metastasis, highlighting Silmitasertib as a potential therapeutic agent."

Journal • Genito-urinary Cancer • Infectious Disease • Oncology • Penile Cancer • Solid Tumor • Squamous Cell Carcinoma • MMP3 • SPP1

Spatio-temporal Progression of Focal Ischemic White Matter Injury (ISC 2025) - "We established MRI modalities to longitudinally assess WMI damage which correlates with behavioral deficits and cellular and molecular damage. Additionally, we showed that CX-4945 exerts post-ischemic protection of WM integrity quantified with MRI images, decreased NOX activity, and improved mitochondrial function."

Late-breaking abstract • Cardiovascular • Ischemic stroke • Metabolic Disorders

CK2 inhibition as a promising treatment for chemotherapy resistant pancreatic ductal adenocarcinoma (LCC 2025) - "Using the first-in-class, CK2-selective inhibitor CX-4945/Silmitasertib, shown to be safe and well-tolerated in phase I/II clinical trials for cholangiocarcinoma, medulloblastoma, and basal cell carcinoma7, and well defined in vitro and in vivo models of PDAC validated in our laboratory, we aim to investigate the impact of CK2 inhibition on PDAC tumorigenesis, metastasis, chemoresistance, and immune infiltration...Notably, nuclear accumulation of CK2 is a reliable predictor of poor prognosis8. We hypothesise that inhibition of CK2 will reduce metastasis and improve overall survival in in vitro and in vivo models of PDAC by sensitising PDAC cells to the latest clinically used chemotherapies by inhibiting CK2-driven DNA damage repair pathways, and promoting activation of the existing immune system."

IO biomarker • Basal Cell Carcinoma • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Medulloblastoma • Non-melanoma Skin Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Phosphoproteomic analysis identifies casein kinase II and MAPK signaling inhibition as a therapeutic strategy for metastatic colorectal cancer (LCC 2025) - "In particular, the combination between silmitasertib and trametinib, a selective inhibitor of MEK1/2, induced a simultaneous reduction of mTORC1, MAPK and CKII signaling compared to either drug alone. Additionally, the dual therapy significantly reduced active β-catenin levels and decreased the pool of CD44/CD133 double-positive cancer stem cells, which are critical in therapy resistance. Taken together, our findings highlight the potential of phosphoproteomic analysis to strategically inform and advance cancer therapy and propose a promising new therapeutic opportunity for mCRC patients, warranting further preclinical and clinical investigations."

Metastases • Omic analysis • Colorectal Cancer • Oncology • Solid Tumor • CD133 • KRAS

Targeting the IKZF1/BCL-2 axis as a novel therapeutic strategy for treating acute T-cell lymphoblastic leukemia. (PubMed, Cancer Biol Ther) - "In vivo studies with cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models demonstrated that CX-4945 and venetoclax combined therapy provided superior therapeutic efficacy, reducing tumor burden and prolonging survival compared to single-agent treatments. IKZF1 represses BCL-2 in T-ALL, and targeting the CK2-IKZF1 axis with CX-4945 and venetoclax offers a promising therapeutic strategy, showing enhanced efficacy and potential as a novel treatment approach for T-ALL."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • IKZF1

Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: Pediatric Brain Tumor Consortium | Suspended ➔ Recruiting | Trial completion date: Feb 2029 ➔ Feb 2030 | Trial primary completion date: Dec 2028 ➔ Dec 2029

Enrollment open • Trial completion date • Trial primary completion date • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Protective effect of CK2 against endoplasmic reticulum stress in pancreatic β cells. (PubMed, Diabetol Int) - "In the present study, we aimed to clarify the mechanisms underlying the effect of CK2 on pancreatic β cells using a CK2-specific inhibitor, CX4945, and shRNA-mediated knockdown and overexpression of CK2β, the regulatory subunit of CK2...Therefore, CK2 activation could be a promising novel approach for preventing type 2 diabetes. The online version contains supplementary material available at 10.1007/s13340-024-00775-w."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • HSPA5

Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression. (PubMed, Cancer Res) - "Casein kinase 2 (CK2) directly phosphorylated SLC16A3 at S436, and CK2 inhibition with CX-4945 (silmitasertib) reduced the growth of KRAS-mutated iCCA tumor xenografts and patient-derived organoids. Together, this study provides valuable insights into the diverse functions of SLC16A3 in iCCA and comprehensively elucidates the upstream regulatory mechanisms, providing potential therapeutic strategies for iCCA patients with KRAS mutations."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • AKT1 • HIF1A • KRAS • SLC16A3 • SLC16A4

CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions. (PubMed, Cell Death Dis) - "Pharmacological inhibition of Casein kinase II by Silmitasertib or genetic depletion of the catalytic subunit of Casein kinase II (CK2α) markedly destabilizes YAP1 and consequently suppresses its oncogenic functions in vitro and in vivo...Notably, upregulated expressions of CK2α and DUB3 in ovarian cancer positively correlate with YAP1 overexpression. Collectively, our findings demonstrate the functional significance of the CK2α-DUB3 axis in YAP1 stabilization and YAP1-driven tumor progression, highlighting that strategies to target this axis might be of benefit in the clinical management of ovarian cancer and several other lethal cancers with aberrantly upregulated YAP1."

Journal • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • YAP1

Targeting WDR5/ATAD2 signaling by the CK2/Ikaros axis demonstrates therapeutic efficacy in T-ALL. (PubMed, Blood) - "Lastly, combining CX-4945 with WDR5 inhibitor demonstrates synergistic efficacy in the patient-derived xenograft mouse models. In conclusion, our results demonstrated that WDR5/ATAD2 is a new oncogenic signaling pathway in T-ALL, and simultaneous targeting of WRD5 and CK2/IKAROS has synergistic anti-leukemic efficacy and represents a promising potential strategy for T-ALL therapy."

Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • IKZF1 • WDR5

Casein Kinase 2 Inhibitor, CX-4945, Induces Apoptosis and Restores Blood-Brain Barrier Homeostasis in In Vitro and In Vivo Models of Glioblastoma. (PubMed, Cancers (Basel)) - "Furthermore, in confirmation of the in vitro study, performing a xenograft model, we demonstrated that CX-4945 exerted promising antiproliferative effects, also restoring the tight junctions' expression. These new insights into the molecular signaling of CK2 in GBM and BBB demonstrate that CX-4945 could be a promising approach for future GBM therapy, not only in the tumor microenvironment but also at the BBB level."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Targeted Therapy with CX4945 Biomimetic Nanodrug Delivery System for High-Risk B-Cell Acute Lymphoblastic Leukemia (ASH 2024) - "CX4945@PLGA-PEG@CM NPs is a biomimetic nanodrug with a core-shell structure, which has high stability and biocompatibility to delay the release of CX4945 drug and improve the bioavailability of the drug. Our study not only provides the evidence to get a better CK2 inhibitor for the therapy of B-ALL but also provides a theoretical basis using a biomimetic nano-delivery system to optimize drug treatment and even a new possibility for hematological drug research."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Inflammatory Arthritis • Leukemia • Oncology • CXCL12 • CXCR4 • IKZF1

Body weight control via protein kinase CK2: diet-induced obesity counteracted by pharmacological targeting. (PubMed, Metabolism) - "Taken together, our study provides novel insights into the role of CK2 in fat metabolism in response to chronic lipid overload and confirms CK2 pharmacological targeting as a potentially powerful strategy for body weight control and/or the treatment of obesity and related metabolic disorders."

Journal • Genetic Disorders • Metabolic Disorders • Obesity

Phosphoproteomics guides low dose drug combination of cisplatin and silmitasertib against concurrent chemoradiation resistant cervical cancer. (PubMed, Mol Omics) - "Our findings highlight the potential of phosphoproteomics to identify clinically significant targets and pathways implicated in CCRT resistance. Our study also indicates that combination therapy could serve as an effective treatment strategy to improve the efficacy of patients undergoing CCRT."

Journal • Cervical Cancer • Oncology • Solid Tumor • CDK1 • PLK1 • PRKDC

Synergistic Effect of CK2 Inhibitor CX-4945 with HDACi Chidamide in B-Cell Acute Lymphoblastic Leukemia By Downregulating TCL1A Expression (ASH 2024) - "Moreover, TCL1A knockdown significantly suppresses the proliferation of B-ALL cell lines (p<0.05).Conclusion Our results indicate that the combination of CX-4945 and CHI exerts an anti-leukemic effect by suppressing TCL1A expression in B-ALL. Our study reveals a new potential combination therapy for high-risk B-ALL."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ANXA5 • IKZF1 • TCL1A

Casein Kinase 2 Inhibitor, CX-4945, Induces Apoptosis and Restores Blood-Brain Barrier Homeostasis in In Vitro and In Vivo Models of Glioblastoma (Multidisciplinary Digital Publishing Institute) - "We reported that CX-4945 reduced the proliferative activity and modulated the main pathways involved in tumor progression including apoptosis. Furthermore, in confirmation of the in vitro study, performing a xenograft model, we demonstrated that CX-4945 exerted promising antiproliferative effects, also restoring the tight junctions’ expression."

Preclinical • Glioblastoma

Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold. (PubMed, Eur J Med Chem) - "Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range."

Journal • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Oncology • Renal Cell Carcinoma • Solid Tumor

Phosphoproteomic Mass Spectrometry Reveals A Novel Therapeutic Target in Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (NANETS 2024) - "We selected CX-4945 (silmitasertib), a casein-kinase 2 inhibitor, for PDO validation, as CK1 has no available clinically relevant inhibitors...CONCLUSIONS Phospho-MS reveals novel signal dysregulation in well-differentiated GEP-NET liver metastases. Our data suggests that CK-2 inhibition has potential efficacy for Grade I and Grade II SBNETs and PNETs."

Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor

Shifting from Epigenetics to the Epichaperome: HSP90 as a therapeutic target for H3K27M Diffuse Midline Glioma (DMG) (SNO 2024) - "HSP90 inhibitors, PU-H71 and PU-HZ151, effectively reduced viability of DMG lines in vitro in the low nanomolar range and result in caspase mediated cell death (p<0.0001 1 uM, p<0.05 500 nM, n=6). To enhance the therapeutic efficacy of epichaperome inhibition, we employed the CSNK2A1 kinase inhibitor, CX-4945, in combination with PU-HZ151, resulting in the effective ablation of DMG patient cells in vitro. These data highlight the potential of epichaperome inhibitors for DMG treatment, as they target multiple DMG oncogenic pathways."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CDC37 • HSF1 • HSP90AA1

Senhwa Biosciences announces first patient dosed in the Phase I/II study of Silmitasertib in children and young adults with relapsed refractory solid tumors (PRNewswire) - "Senhwa Biosciences...announced that the enrollment of the first patient at Penn State Health Children's Hospital in its Phase I/II clinical study evaluating the efficacy of Silmitasertib (CX-4945) in combination with chemotherapy for children and young adults with relapsed or refractory solid tumors. This innovative trial seeks to establish a recommended dose of Silmitasertib in combination with chemotherapy and assess the safety, tolerability and efficacy in patients with cancer, with a focus on neuroblastoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, and liposarcoma....The study is projected to enroll up to 114 participants nationwide through the Beat Childhood Cancer Research Consortium member hospitals."

Trial status • Ewing Sarcoma • Liposarcoma • Neuroblastoma • Osteosarcoma • Rhabdomyosarcoma

CK2 FAVORS T-CELL CHEMOTAXIS THROUGHT THE RELEASE OF SOLUBLE FACTORS BY HODGKIN AND REED–STERNBERG CELLS (ISHL 2024) - "In this study, we assess the role of protein CK2 in sustaining T-cell recruitment in the tumor niche.HL cell lines (KM-H2 and HDLM-2) were treated with 0, 5, and 10 μM of CX-4945 (CX), a CK2 inhibitor, for 24/48 h. Apoptosis was quantified by flow cytometry with the Annexin V/Propidium iodide assay...Among the tested cytokines, IL-6, M-CSF, RANTES, TARC, TGF-β1, TNF-α, and VEGF, demonstrated a significant CK2 dependence. When HL cell lines were treated with 10 μM CX, there was a significant reduction of IL-6, TARC, TGF-β1, TNF-α, and VEGF release (p < 0.0001) and for some molecules also at 5 μM.We also found that CM from HL cell lines was able to modulate the expression of the T-cell surface receptor CXCR3 but not CCR7, assessed by WB (p < 0.05), compared the untreated condition, which was not observed with the CM derived from CX-treated HL cells.In conclusion, CK2 emerged as a novel player in the formation of HL microenvironment by modulating the release of..."

Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Oncology • ANXA5 • CCR7 • CSF1 • CXCR3 • IL6 • STAT3 • TGFB1 • TNFA

Cisplatin-resistance and aggressiveness are enhanced by a highly stable endothelin-converting enzyme-1c in lung cancer cells. (PubMed, Biol Res) - "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."

Journal • Brain Cancer • CNS Tumor • Colorectal Cancer • Gastrointestinal Cancer • Glioblastoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ABCG2 • CD133 • EDN1 • MYC • POU5F1 • SOX2 • UBB

Silmitasertib (CX-4945) in Combination with Chemotherapy for Relapsed Refractory Solid Tumors (clinicaltrials.gov) - P1/2 | N=114 | Recruiting | Sponsor: Milton S. Hershey Medical Center | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • CNS Tumor • Ewing Sarcoma • Liposarcoma • Neuroblastoma • Oncology • Osteosarcoma • Rhabdomyosarcoma • Sarcoma • Solid Tumor