CK2 Inhibitor Program - CX-4945
CX-4945, a synthetically derived small molecule, is provided as sodium salt in hard gelatin capsule shells with oral administration.
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.
Normal cells with DNA that do not replicate rapidly, as in fast growing cancer cells, and cells that have all of their DNA repair mechanisms intact are able to survive the temporary shutdown of one or more of these pathways. Inhibiting CK2 has been shown to inhibit DNA repair, and this augments the lethality of the DNA damage in cancer cells that is caused by chemotherapy treatment.
CX-4945 is a selective, small molecule inhibitor of CK2. It has demonstrated favorable safety, pharmacokinetic (PK) characteristics and pharmacodynamics (PD) responses in Phase I studies.
Clinical observations show that CX-4945 hits the CK2 target and modulates the expected pathways without displaying toxicity. CX-4945 achieved clinical benefit as a single agent CK2 inhibitor, demonstrating stable disease and extended duration on treatment in a several patients. A combination of CX-4945 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. This combination is currently being developed for the treatment of advanced cholangiocarcinoma, a disease for which there are no currently effective therapies.
DNA-targeted chemotherapy is the main treatment modality currently available. The cytotoxicity of many of these chemotherapy agents (Cisplatin, Gemcitabine, etc.) is directly related to their propensity to induce DNA damage. However, the ability of cancer cells to recognize this damage and initiate DNA repair is an important mechanism of drug resistance and has a negative impact on the therapeutic efficacy. CX-4945, an inhibitor of CK2, decreases XRCC1 and MDC1 phosphorylation, two nuclear proteins that play a key role in the repair of DNA single-strand and double-strand breaks, respectively, and that require phosphorylation by CK2 for their function. Therefore, CX-4945 in combination with Cisp/Gem inhibits DNA break repair, and causes death of cancer cells.