Fragment- and structure-based drug discovery technologies were employed in a two-year-long research project into the Chk1 pathway, and V158411 is the lead molecule delivered by that project.
Chk1 inhibitors have the potential to improve the effectiveness against cancer cells of a range of cytotoxic agents, such as gemcitabine and irinotecan. Chk1 inhibitors aim to exploit differences in “checkpoint” pathways between cancer and normal cells so that the cytotoxic agents become more lethal to cancer cells, without increasing their toxicity to normal cells. If this effect is proven, Chk1 inhibitors could prove effective in a wide range of solid tumours and haematological cancers.
Some cancer cells use the Chk1 pathway to increase cell survival by pausing DNA replication and allowing repair of the damaged DNA before completing cell division. Inhibition of Chk1 blocks this pathway, forcing cells to undergo cell division (mitosis) with substantial DNA damage that results in their death. Our research aimed to identify product candidates that increase the anti-tumour efficacy of current cytotoxic agents without increasing their toxicity to non-cancerous tissues. Because Chk1 inhibitors are used in conjunction with chemotherapy drugs, they can potentially be used to treat a broad range of tumour types including breast, prostate, colorectal and melanoma. They may also be used in haematological cancers such as leukaemia.
V158411 has shown efficacy in both in vitro and in vivo evaluations in a range of different tumour types, in combination with several different cytotoxic agents. Chk1 inhibitors have the potential to improve the effects of a range of DNA damaging cytotoxic agents and consequently have potential utility in a broad range of solid tumours and haematological cancers.
Pre-clinical studies to enable filing of an IND or CTA were completed successfully in 2012 and the compound is now ready to progress into clinical development. However, further development of V158411 is expected to be undertaken with a partner and a partnering process continues.