Introduction

CK2 (Casein kinase 2) is a protein kinase that has elevated activity in many cancers and has a direct role in DNA damage repair. The DNA repair pathways enable tumor cells to survive damage induced by treatment with chemotherapeutic agents. Inhibitors of DNA repair pathways have been shown to increase the efficacy of DNA-damaging chemotherapeutic drugs when these are used in combination.

Oncology

Silmitasertib is a first-in-class potent and highly selective inhibitor for CK2. It has demonstrated favorable safety, pharmacokinetic (PK) characteristics and pharmacodynamics (PD) responses in clinical studies.

Clinical observations show that Silmitasertib hits the CK2 target and modulates the expected pathways without displaying toxicity. Silmitasertib achieved clinical benefit as a single agent CK2 inhibitor. A combination of Silmitasertib with the DNA damaging agents such as gemcitabine (Gemzar) plus cisplatin (Platinol), has been shown to act synergistically to improve the efficacy of these anticancer treatments.

Infectious Disease

Silmitasertib is a promising therapeutic due to its dual impact on COVID-19:

• Block SARS-CoV-2-induced CK2 overactivation required for active viral replication and spread to nearby cells.
• Reduce cytokine storm severity by interrupting cytokine signaling pathway.

Silmitasetib interacts competitively with the ATP-binding site of CK2 subunit alpha, leading towards the inhibition of several downstream signaling pathways:

• CK2 inhibition reduces virus assembling, directly controls viral replication.
• CK2 inhibition reduces Stress Granule (SG) disassembly resulting in inhibition of virus replication.
• CK2 inhibition downregulates filopodia formation.
• In preclinical and clinical studies, Silmitasertib was found to significantly reduce plasma levels of IL-6, IL-8 and IL-17 in diseases with elevated cytokine levels (inflammatory breast cancer, autoimmune diseases, Alzheimer's disease).
• Inhibition of CK2 leads to restoring of type I interferons production during RNA virus infection.

Silmitasertib demonstrated anti-viral and anti-inflammatory efficacy in COVID-19 in vitro studies. As it targets host protein kinase CK2, SARS-CoV-2 virus mutations are unlikely to affect Silmitasertib anti-viral efficacy.

Please find more details of Silmitasertib's dual MOA (Mechanism of Action) and developments in the attached file, below.

Details of Silmitasertib’s dual MOA (Mechanism of Action)  and Developments