Investigating compounds to treat Colorectal cancer by targeting Siglec-15

According to recent statistics, colorectal cancer (CRC) is 4th most common type of cancer and 3rd most lethal type of cancer. In the UK alone, around 43,000 people are diagnosed with this type of cancer per year. With the best possible therapy, the 5-year survival time of CRC patients is 60%. Moreover, the survivors suffer from extreme toxicity/side effects associated with the current extreme is highly devastating. The main reason for the toxicity of the current therapy is the fact that the drug molecules work on the targets that are not only expressed by the cancer cells but also by the normal healthy cells. Therefore, there is a need to develop therapies that work on the molecules expressed exclusively/majorly on cancer cells. In this project, we will target Siglec-15, which is an immune checkpoint and oncogene expressed by cancer cells, with minimal expression on normal healthy cells (Zhou et al., 2023). Siglec-15 binds with ligands (sialic acid) expressed by the T cells leading to intracellular signalling, thus dampening the immune response against cancer. The blocking antibodies against Siglec-15 are in clinical phase II trials for several types of cancer, such as ovarian cancer, lung cancer, melanoma and CRC ((Stanczak & Läubli, 2023), NCT03665285, NCT04699123)). Recently, we reported SHG-8 (a β-amino ketone), which is the first small molecule inhibitor that targets Siglec-15 (Ahmad et al., 2023). In addition, using a virtual screening platform, we identified a drug molecule (mk-3207) that has been used in clinical trials against migraine (Hewitt et al., 2011) as an inhibitor of Siglec-15. Our preliminary results showed that mk-3207 binds to arginine-143 of Siglec-15, which can block the binding with sialic acid ligands. In this project, we will decipher the role of mk-3207 as an anti-cancer agent for CRC.