Therapeutic covalent ligands for targeted cancer therapy

As compared to chemotherapy, targeted therapy is generally more specific and shows less toxic side effects, and is considered to be a better treatment option to cancer patients. Nonetheless, only a small population of cancer driver proteins have been drugged by targeted therapeutic agents, thus not much alternative treatment options are available when drug resistance develops or poor prognosis is found. This limitation can be explained by the fact that close to 90% of human proteins have been found to be lack of nice and deep pockets for drug compound binding, and they were once considered as undruggable.

Recently, covalent drugs have been successfully developed to target G12C mutation in KRAS, one of the most famous undruggable proteins. This motivates us to explore covalent ligands to target new cancer driver proteins and investigate their potential applications for targeted cancer therapy. Through chemoproteomics-enabled screening platform, we have identified novel covalent ligands targeting different cancer driver proteins which have not been drugged so far. By integrative chemical biology and MS-based ABPP experiments, we have confirmed the specific binding of the covalent ligands on the cancer driver proteins in cancer cells. Some of the covalent ligands have been found to show promising in vivo antitumor effects, demonstrating the good potential of using these compounds for targeted cancer therapy.