silmitasertib (CX-4945)

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

P2, N=45, Terminated, Senhwa Biosciences, Inc. | N=136 --> 45 | Recruiting --> Terminated; The trial ended early in March 2025 due to changes in disease epidemiology, affecting patient availability and recruitment feasibility.

KD025(belumosudil), a selective ROCK2 inhibitor, exhibits unique anti-adipogenic activity through inhibition of casein kinase 2 (CK2)...C57BL/6 mice on a high fat diet (HFD) were treated with KD025 for 4 weeks, while fasudil (a pan-ROCK inhibitor) and CX-4945 (a CK2-specific inhibitor) served as comparison treatments...Furthermore, KD025 and CX-4945 upregulated adipogenic and browning markers, such as Cebpa, Cidea, and Pparg, in the epiWAT, though without significant UCP1 expression. Overall, KD025 effectively reduced weight gain in HFD-fed mice through dual inhibition of CK2 and ROCK2, highlighting its potential as a therapeutic agent for obesity-related conditions.

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.

P1/2, N=66, Recruiting, Pediatric Brain Tumor Consortium | Suspended --> Recruiting | Trial completion date: Feb 2029 --> Feb 2030 | Trial primary completion date: Dec 2028 --> Dec 2029

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.

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.