New lead compounds for treating cancers involving Ras mutations

In the UK, over 350,000 people are diagnosed with cancer each year. Approximately 20% of these tumours are caused by genetic mutations that permanently activate Ras, making it a key drug target in oncology. Ras are a family of proteins involved in the activation of cell growth and cell survival genes. Activated Ras leads to multiple downstream protein-protein interactions that ultimately result in the transcription of a number of genes that promote cell growth and survival.

Researchers at the University of Oxford have devised a method of obtaining small molecules that have the same properties as larger, validated Ras inhibitors that are unable to access the intracellular targets. These small molecules are able to bind to Ras and prevent further protein-protein interactions, inhibiting the activation of oncogenic genes commonly associated with cancer proliferation.

Cancer is a major global disease burden, costing the NHS approximately £5bn a year. Around 97% of pancreatic cancer and 45% of colorectal cancer are the result of Ras family gene mutations, and a number of other cancers are linked to Ras mutations, making it a key drug target for cancer therapy.

Methods for treating cancer

Attempts to develop drugs that target mutant Ras have so far been unsuccessful, meaning tumours bearing this mutation remain the hardest to treat. Small molecules are able to readily penetrate cells, however, were not initially thought to be able to interfere with protein-protein interactions.

Such small molecules have been discovered by identifying antibody fragments capable of binding to Ras and using their structure to derive smaller compounds that mimic their properties. The antibody fragments are therapeutically ineffective without intracellular delivery, as they are unable to penetrate the cell membrane to reach their targets.

Development of Ras inhibitors

Researchers from the University of Oxford have found numerous small molecule Ras inhibitors, the most potent of which has been shown to effectively block protein-protein interactions between Ras and effector molecules in cell-based assays.

These unique small molecules offer potential therapy for those suffering from mutated Ras-related cancers where there is currently no treatment available.

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