Development of novel direct inhibitors of KRAS mutants as anticancer agent
Inhibitors that target the oncogene KRAS in three different cancers have been developed at McGill University.
Since cellular functions such as apoptosis and proliferation are regularly targeted for oncogenic mutations, there are several gene families that are mutationally altered across different cancers. One of the most commonly mutated genes in human cancers is the oncogene KRAS, a cell membrane GTPase protein that activates numerous cellular pathways. Specifically, oncogenic KRAS is mutationally activated in 90% of pancreatic ductal adenocarcinoma (KRAS 12D), 50% of colorectal cancer (KRAS 12D/V), and 25% of non-small cell lung cancer (KRAS 12C). However, there have been no clinically successful attempts to directly target KRAS mutations or its binding partners.
In this invention, novel inhibitors were discovered that target KRAS 12D (pancreatic cancer), KRAS12 V (colorectal cancer), and KRAS 12C (lung cancer), but were inactive against wild-type KRAS. After screening a unique binding pocket for potential therapeutic agents, top-ranking candidates were verified by a variety of assays for effectiveness and inhibition of cancer cell proliferation. Two of the compounds directly target KRAS mutations in multiple cancers and were confirmed by surface plasmon resonance analysis. With the ability to inhibit KRAS in three major cancer types, these chemical compounds could be very important to the field of cancer therapy.
- Directly targets the KRAS 12D mutant, as well as the 12V and 12C mutant
- Therapeutic agents for the treatment of 3 cancers
- Pancreatic ductal adenocarcinoma
- Colorectal cancer
- Non-small cell lung cancer
Filed EP, US, CA