作者: da Silveira Hahmeyer, Maria Luísa ; Collino, Massimo ; Porchietto, Elisa ; da Silva-Santos, José Eduardo ; Aragno, Manuela ; Fernandes, Daniel ; Marzani, Enrica ; Einaudi, Giacomo ; Cifani, Carlo ; Aimaretti, Eleonora ; Rubeo, Chiara ; Ferreira Alves, Gustavo

Casein kinase II (CK2) has recently emerged as a pivotal mediator in the propagation of inflammation across various diseases. Nevertheless, its role in the pathogenesis of sepsis remains unexplored. Here, we investigated the involvement of CK2 in sepsis progression and the potential beneficial effects of silmitasertib, a selective and potent CK2α inhibitor, currently under clinical trials for COVID-19 and cancer. Sepsis was induced by caecal ligation and puncture (CLP) in four-month-old C57BL/6OlaHsd mice. One hour after the CLP/Sham procedure, animals were assigned to receive silmitasertib (50 mg/kg/i.v.) or vehicle. Plasma/organs were collected at 24 h for analysis. A second set of experiments was performed for survival rate over 120 h. Septic mice developed multiorgan failure, including renal dysfunction due to hypoperfusion (reduced renal blood flow) and increased plasma levels of creatinine. Renal derangements were associated with local overactivation of CK2, and downstream activation of the NF-ĸB-iNOS-NO axis, paralleled by a systemic cytokine storm. Interestingly, all markers of injury/inflammation were mitigated following silmitasertib administration. Additionally, when compared to sham-operated mice, sepsis led to vascular hyporesponsiveness due to an aberrant systemic and local release of NO. Silmitasertib restored sepsis-induced vascular abnormalities. Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis.

2024-09-01·Chemical and Pharmaceutical Bulletin

Compounds Designs of CK2α Inhibitors Derived from Virtual Screening Hit Compounds by Computational Chemistry with Crystallography

Review

作者: Kinoshita, Takayoshi ; Ohno, Hiroaki ; Nakanishi, Isao ; Oishi, Shinya ; Nakamura, Shinya ; Tsuyuguchi, Masato ; Nishiwaki, Keiji

Protein kinase CK2 type α (CK2α) inhibitors are expected to be a new anticancer drug and a treatment for nephritis. Virtual screening for CK2α inhibitors has been conducted and active compounds with various scaffolds have been obtained. Research on compound optimization is currently in progress for some of them with the aim of improving their activity. This process involves the combination of various computational chemistry methods and crystal analyses. In this review, case studies of structure-based compound designs that have efficiently improved the activity of screening hit compounds, including compounds with a thiadiazole ring and a purine scaffold, are introduced.

2024-08-01·International Immunopharmacology

A quinolinyl resveratrol derivative alleviates acute ischemic stroke injury by promoting mitophagy for neuroprotection via targeting CK2α’

Article

作者: Liu, Yueyang ; Meng, Qingqi ; Hou, Yue ; Yang, Yuxin ; Mi, Yan ; Zhang, Ying ; Chen, Guoliang ; Liu, Yeshu ; Wang, Yongping ; Xu, Libin

Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.

项与 CK2α抑制剂(Apollo Therapeutics) 相关的新闻（医药）

2024-07-12

·PRNewswire

Senhwa Biosciences Announces IND Submission to US FDA for the Phase I/II study of Silmitasertib (CX-4945) in children and young adults with relapsed refractory solid tumors

TAIPEI, July 11, 2024 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), announced IND Submission to US FDA for the Phase I/II study of Silmitasertib (CX-4945) in combination with chemotherapy in children and young adults with relapsed refractory solid tumors. This investigator-initiated trial (IIT) will be conducted by the Penn State Health Children's Hospital and the prestigious Beat Childhood Cancer Research Consortium, a group of over 50 universities and children's hospitals, based at Penn State College of Medicine in Hershey, Pa., that offers a worldwide network of pediatric cancer clinical trials. The funding is sponsored by the Four Diamonds Foundation, with Senhwa Biosciences providing the investigational drug, Silmitasertib (CX-4945). The clinical trial is conducted in two phases: the first phase focuses on establishing the safety and dosage of Silmitasertib (CX-4945) in pediatric patients with relapsed or refractory solid tumors, while the second phase evaluates its efficacy and potential as a novel treatment option. As high CK2 activity is noted across several pediatric cancers, including neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, medulloblastoma, and liposarcoma. Recent study has shown that CK2 is one of the key kinases that is essential for maintaining the stabilization of MYCN protein, the oncogenic driver in neuroblastoma. In view of the anti-tumor activity of CK2 inhibitor, the Beat Childhood Cancer Research Consortium at The Pennsylvania State University regards Silmitasertib (CX-4945) high therapeutic potential of treating pediatric cancers. Neuroblastoma is the most common type of solid malignant tumor in children, aside from brain tumors and lymphomas. Over 90% of cases are diagnosed before the age of 5. 70% of patients already have metastatic disease by the time symptoms appear, and the 20-year survival rate is only around 30%. In the US, there are 700-800 new cases each year, accounting for about 6% of childhood cancers, meeting the definition of a rare disease. Senhwa Biosciences is planning to apply for Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPD) for Silmitasertib (CX-4945) for the treatment of neuroblastoma. If these designations are granted and the drug is successfully commercialized, the company would obtain a Priority Review Voucher (PRV). The holder of a PRV can designate any future human drug application to receive priority review, potentially shortening the review time to 6 months, which could accelerate the timeline for the company (or its partners) to bring other products to market. The clinical trial design also includes Ewing's sarcoma and osteosarcoma, which are common pediatric bone cancers with poor prognoses, representing unmet medical needs. SOURCE Senhwa Biosciences, Inc.

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