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

Targeting the casein kinase II /ikaros axis sensitizes TKI activity by suppression of GLUT1 expression and glycolysis in ph+ ALL (ASH 2025) - "Results showed that the combination of various doses of TKI Imatinib orPonatinib with 2.5 μM (1/2 IC50) or 5 μM (IC50) CX-4945 showed significant synergistic effects on the cellproliferation arrest of Sup-B15 cells (CalcuSyn analysis CI < 1, and the Bliss model synergy score of 6.617or 5.885, respectively). CX-4945 sensitizes the sensitivity of TKI activity in Ph+ALL, particularly with IKZF1 deletion,by affecting GLUT1 expression and glycolysis. Our findings reveal the potential of the new combination inthe therapy of ALL patients."

Acute Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • ANXA5 • IKZF1 • PTPRC • SLC2A1

Combined Inhibition of Protein Kinase CSNK2 and BET Proteins As a Novel Therapeutic Strategy for Mantle Cell Lymphoma (ASH 2023) - "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."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • ANXA5 • BRD4 • MYC

Silmitasertib, an FDA-designated orphan CK2 Inhibitor, ameliorates neuropathology and motor dysfunction in a Huntington's disease mouse model. (PubMed, bioRxiv) - "Importantly, we found CX-4945 decreased mHtt aggregation, increased DARPP-32 expression and excitatory synapse density, restored homeostatic astrocyte phenotypes and ameliorated neuroinflammation and microgliosis, altogether resulting in improved motor behavior. These results support CX-4945 as a strong candidate for a targeted therapy to treat HD."

Journal • Preclinical • CNS Disorders • Huntington's Disease • Inflammation • Movement Disorders

Macropinocytosis as a novel target for pediatric high grade glioma therapy (SNO 2025) - "In addition, silmitasertib synergizes with temozolomide to decrease cell proliferation (ZIP synergy score = 15.23). These findings suggest that pHGGs undergo macropinocytosis in vitro and targeting this pathway may be an additional avenue for therapy. In addition, to further understand the genetic signatures underlying macropinocytosis, we are currently conducting a targeted CRISPR screen with an endocytosis, macropinocytosis, phagocytosis, and lysosomal processing library."

Clinical • Brain Cancer • Glioma • High Grade Glioma • Pediatrics • Solid Tumor

Synergistic Effect of CK2 Inhibitor CX-4945 with HDACi Chidamide on Cell Proliferation Arrest and Apoptosis in Acute Myeloid Leukemia (ASH 2023) - "Our data provide experimental evidence for the combination as a potential option for AML therapy. More pre-clinical studies will be explored for future clinical trials."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • IKZF1 • MYC • PIK3CD

Scaling Large Language Models for Next-Generation Single-Cell Analysis. (PubMed, bioRxiv) - "This predictive strength directly enabled a dual-context virtual screen that uncovered a striking context split for the kinase inhibitor silmitasertib (CX-4945), suggesting its potential as a synergistic, interferon-conditional amplifier of antigen presentation. Experimental validation in human cell models unseen during training confirmed this hypothesis, demonstrating that C2S-Scale can generate biologically grounded, testable discoveries of context-conditioned biology. C2S-Scale unifies transcriptomic and textual data at unprecedented scales, surpassing both specialized single-cell models and general-purpose LLMs to provide a platform for next-generation single-cell analysis and the development of "virtual cells.""

Journal

Macropinocytosis as a novel target for pediatric high grade glioma therapy (WFNOS 2025) - "In addition, silmitasertib synergizes with temozolomide to decrease cell proliferation (ZIP synergy score = 15.23). These findings suggest that pHGGs undergo macropinocytosis in vitro and targeting this pathway may be an additional avenue for therapy. In addition, to further understand the genetic signatures underlying macropinocytosis, we are currently conducting a targeted CRISPR screen with an endocytosis, macropinocytosis, phagocytosis, and lysosomal processing library."

Clinical • Brain Cancer • Glioma • High Grade Glioma • Pediatrics • Solid Tumor

Casein Kinase II Inhibitor Sensitizes the Anti-Tumor Effect of EZH2 Inhibitor By Suppressing FOSL1 Expression in Acute Myeloid Leukemia (ASH 2023) - "The present study aims to investigate the effect of the combination of the EZH2 inhibitor DZNeP with CK2 inhibitor CX4945 in AML and possible underlying mechanisms...Our results reveal the oncogenic role of FOSL1 in AML. Our data also provide experimental hints for the potential clinical trial of the novel combination in AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • EZH2 • FOSL1

Suppressing IKZF1 Deletion-Mediated Activation of Ras Oncogenic Signaling By the Combination of Azacitidine and Flumatinib in High-Risk B-ALL (ASH 2023) - "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."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CDKN1A • IKZF1 • PTPN11

Dual Targeting Novel WDR5/ATAD2 Oncogenic Signaling through CK2/Ikaros Axis Demonstrates Synergistic Efficacy in T-ALL (ASH 2023) - "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."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ATAD2 • IKZF1 • PTPRC • WDR5

Selinexor Synergizes CX4945 on Anti-Tumor Effect By Targeting XPO1/Ikros/c-Myc Signaling in T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "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."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ANXA5 • IKZF1 • XPO1

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 Malignancies • Leukemia • Oncology • ANXA5 • IKZF1 • TCL1A

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 Malignancies • Inflammatory Arthritis • Leukemia • Oncology • CXCL12 • CXCR4 • IKZF1

HERPUD1 mediates palmitic acid-induced UPR sustaining TNBC aggressiveness and is destabilized by CK2 pharmacological inhibition. (PubMed, Cell Death Dis) - "HERPUD1 silencing reduced TNBC cell proliferation, migration, and invasion while enhancing doxorubicin (DOX) cytotoxicity, in both 2D and 3D cell culture models. Strikingly, inhibition of CK2 with CX-4945 not only reduced HERPUD1 levels but also increased the sensitivity of BC cells to DOX. HERPUD1-S59D phosphomimetic mutants showed opposite effects.Our findings establish HERPUD1 as a key mediator of PA-driven aggressiveness, dependent on the lipid-handling capacity of TNBC cells and reveals a mechanistic to lipid stress and tumor progression."

Journal • Breast Cancer • Genetic Disorders • Obesity • Oncology • Solid Tumor • Triple Negative Breast Cancer • ATF4 • CXCL8 • IL6

NOVEL COMBINATION THERAPY TARGETING POLYAMINE PATHWAY IN NEUROBLASTOMA (SIOP 2025) - P1/2 | "Conclusions Results from preclinical studies support clinical testing. An ongoing Phase 1 study evaluates the safety of CX-4945 in relapsed refractory pediatric solid tumors, including NBL (NCT06541262)."

Combination therapy • Neuroblastoma • Pediatrics • Solid Tumor • MYCN

ANTI-TUMOR ACTIVITY OF CK2 INHIBITOR, CX-4945 IN METASTATIC MODELS OF EWING SARCOMA (SIOP 2025) - P1/2 | "Conclusions These results support further preclinical characterization and mechanistic investigation of CX-4945 for treating ES. An ongoing phase 1 clinical trial is evaluating the safety of CX-4945 in pediatric solid tumors, including ES (NCT06541262)."

Metastases • Ewing Sarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • EWSR1 • FLI1 • GLI1

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=21 | Terminated | Sponsor: Pediatric Brain Tumor Consortium | N=66 ➔ 21 | Trial completion date: Feb 2030 ➔ Aug 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Mar 2026 ➔ Aug 2025; The decision to permanently close PBTC-053 was made following communication from the NCI that the PBTC grant will not be extended beyond March 31, 2026.

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

Comparative Efficacy of CK2 Inhibitors CX-4945 and SGC-CK2-2 on CK2 Signaling. (PubMed, Int J Mol Sci) - "The findings of this study demonstrate the differential sensitivity of CK2 phospho-substrates to these inhibitors, thus indicating that complete inhibition of a single phosphosite, such as S129 Akt, is insufficient to fully suppress CK2 signaling. Furthermore, the results suggest that partial CK2 inhibition with the suppression of the most sensitive phosphosites does not significantly impact cell viability, while a near-complete suppression of CK2 signaling affects cell viability and leads to cell death induction."

Clinical • Journal • Infectious Disease • Novel Coronavirus Disease • Oncology

Phosphorylation-induced switch in DEK chromatin occupancy in malignant melanoma cells (ESMO 2025) - "Results By applying a selective CK2 inhibitor, CX-4945 (Silmitasertib), in combination with ChIP-seq and LC-MS/MS analyses, we found that CX-4945 effectively reduced the overall cellular phosphorylation level, and specifically, sites mapped to serines 287 / 288 in DEK in SK-Mel-103 cells...These findings provide a mechanistic basis to further decipher the molecular role of DEK in tumorigenesis. Legal entity responsible for the study The authors."

Melanoma • Oncology • Solid Tumor

Google AI Breakthrough Highlights Silmitasertib (CX-4945) as a Novel Pathway in Cancer Immunotherapy (The Manila Times) - "Through large-scale analysis of tumor cell data and more than 4,000 potential drug candidates, DeepMind's model identified CX-4945 as a key molecule that significantly enhances antigen presentation-a crucial process that enables the immune system to recognize and attack tumor cells."

Clinical • Oncology

CK2 inhibitor CX-4945 targets EWS-FLI1 protein abundance and shows anti-tumor activity in metastatic mouse models of Ewing Sarcoma. (PubMed, bioRxiv) - "CX-4945 showed synergistic cytotoxic activity with Temozolamide and Irinotecan. CX-4945 is currently being tested in a Phase 1 study to evaluate the safety and tolerability in combination with chemotherapy for the treatment of pediatric colloid tumors, including Ewing sarcoma. The preclinical studies reported here support the clinical studies evaluating the efficacy of CX-4945 for the treatment of Ewing sarcoma."

Journal • Preclinical • Ewing Sarcoma • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • Targeted Protein Degradation • EWSR1 • FLI1

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 | Active, not recruiting | Sponsor: Pediatric Brain Tumor Consortium | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Ellagic Acid Mediates the Delay of Dermal Fibroblast Senescence via CSNK2A1. (PubMed, Clin Cosmet Investig Dermatol) - "Senescence was induced in Hs68 cells with H2O2, followed by treatment with EA and CSNK2A1 inhibitor (Silmitasertib)...EA also reduced IL-6, TNF-α, and IL-1β, inhibiting NF-κB p65, with anti-inflammatory effects mediated by CSNK2A1. EA delays dermal fibroblast senescence by modulating CSNK2A1, mitigating oxidative stress and inflammation, and may serve as a potential therapeutic for aging and age-related diseases."

Journal • Inflammation • IL1B • IL6 • NFE2L2 • TNFA • TP53

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 | Active, not recruiting | Sponsor: Pediatric Brain Tumor Consortium | Trial primary completion date: Dec 2029 ➔ Mar 2026

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

Targeting Casein Kinase 2 and Histone Deacetylase with a Dual Inhibitor Effectively Reduces Tumor Growth in a Triple-Negative Breast Cancer Xenograft Model. (PubMed, ACS Pharmacol Transl Sci) - "Furthermore, X-ray crystallography revealed the binding mode of IOR-160 to CK2, showing high conservation compared to that of the known CK2 inhibitor CX-4945. These results suggest that IOR-160 has significant potential as an antitumor agent. Nonclinical and clinical studies become now necessary to validate the efficacy of this new chemical entity as a potential drug."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HDAC8