silmitasertib (CX-4945)

Although ATP-competitive inhibitors such as CX-4945 show therapeutic potential, they are limited by off-target effects and incomplete or transient CK2 suppression...By conjugating a CAM4066-derived warhead to CRBN or VHL ligands, four VHL-recruiting PROTACs, were prepared using PEG and alkyl linkers, alongside two CRBN-recruiting analogues featuring constrained linkers. A ligand-linker analogue in which a linker is projected from the solvent-exposed region of CK2α retained binding affinity comparable to CAM4066, confirming that linker installation is tolerated and preserves key interactions in the αD and ATP sites.

These findings identify CK2 as a key regulator of tumor immune evasion and uncover a previously unrecognized post-translational checkpoint controlling PD-L1 stability via TRAF6-dependent ubiquitination. Targeting CK2 represents a rational strategy to sensitize immunologically "cold" tumors to ICBs and enhance immunotherapeutic efficacy in lung cancer.

The combination of TKIs (imatinib or ponatinib) with CX-4945 significantly extended the survival and reduced the tumor burden in the IKZF1 deletion (Ik6+) Ph+ ALL patient-derived xenograft (PDX) mouse model; particularly, the patient died of relapse shortly after treatment with the third-generation TKI and the CD19/CD3 bispecific antibody blinatumomab. The combination of TKIs with CX-4945 demonstrates the synergistic efficacy through restoring IKAROS transcriptional repression of GLUT1 and further suppressing glycolysis in Ph+ ALL. Our results identify new mechanisms underlying TKI sensitivity and novel approaches to overcome TKI resistance through transcriptional repression of the key genes in glycolysis in Ph+ ALL.

Over the past decades, a wide range of CK2 inhibitors has been developed ranging from classical ATP-competitive scaffolds (TBB, DMAT, CX-4945) to highly selective second-generation chemical probes (SGC-CK2-1, AB668) and substrate-targeting peptides (CIGB-300). Preclinical evidence highlights strong antitumor effects of CK2 blockade in hormone-refractory and triple-negative breast cancer (TNBC), with additional potential to overcome endocrine and chemoresistance. This review integrates recent advances in CK2 biology, summarizes the evolution of CK2 inhibitor classes, and outlines the opportunities and remaining barriers for translating CK2 inhibition into effective cancer therapeutics.

In particular, here we report on the identification of CK2-TN03, a CK2 inhibitor showing greater selectivity and cellular efficacy than silmitasertib, the only available clinical grade CK2 inhibitor with orphan status for cholangiocarcinoma and in clinical trials for medulloblastoma...Accordingly, neuroblastoma cells persistently stall in mitosis before going to apoptosis. Finally, CK2-TN03 does not affect noncycling cells and significantly reduces tumor growth in mice xenografts without any apparent toxicity.

CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy.

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.

P1/2, N=21, Terminated, 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.

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.

P1/2, N=66, Active, not recruiting, Pediatric Brain Tumor Consortium | Trial primary completion date: Dec 2029 --> Mar 2026

P1/2, N=66, Active, not recruiting, Pediatric Brain Tumor Consortium | Recruiting --> Active, not recruiting

P1, N=25, Completed, Senhwa Biosciences, Inc. | Active, not recruiting --> Completed