CV6-168 is a novel small molecule inhibitor of dUTPase that is designed to work in combination with standard-of-care chemotherapies that work by blocking DNA synthesis in cancer cells. These standard-of-care chemotherapies, also known as ‘TS Inhibitors’ work by blocking the cancer cells ability to produce thymine (T), one of the four essential building blocks required for DNA replication alongside Cytosine, C; guanine, G; and adenine, A. When cancer cells are treated with a TS inhibitor, their ability to synthesize DNA is blocked and their growth stops. These treatments however, are only effective in some patients, with many cancers demonstrating ‘resistance’ and finding ways to continue to grow and replicate despite receiving a TS inhibitor. Even in patients where these therapies show promising early activity, oftentimes the surviving cancer cells evolve and develop resistance leading to their continued growth and spread.
CV6-168 transforms the way TS inhibitors work by changing the mechanism of action from one where the TS inhibitor simply starves the cancer cells of a base needed for DNA synthesis, to one that replaces the missing base with an alternative base, uracil, that causes widespread cancer cell DNA damage resulting in enhanced cancer cell death. CV6-168 does this by blocking the action of the enzyme dUTPase, causing the cancer cell to produce a different building block, uracil, that is highly damaging to DNA. When CV6-168 is combined with a TS inhibitor, the cancer cell, unable to distinguish between thymine and uracil, mistakenly uses uracil in place of the depleted thymine for continued DNA replication. When the cancer cell’s DNA repair systems eventually detect the large quantities of detrimental uracil in DNA, the attempted repair of this uracil is so extensive, that it leads to more DNA damage ultimately resulting in the death of the cancer cell. Cancer cells are extremely vulnerable to this approach due to their high rate of uncontrolled replication that is lacking in normal safeguards and checkpoints.
CV6-168 is currently in a Phase 1a clinical trial in the UK. More information on the Phase 1a can be found here: CV6-168 Phase 1a.
