Expanding the targetable landscape in cancer with serine-targeting covalent ligands

Project Summary Targeted covalent inhibitors have empowered the potent and selective targeting of driver oncogenes in cancer. Between 2011 and 2021, 16 new covalent drugs (12 with cancer indications) were approved by the US FDA, with the recent notable example of the first KRAS inhibitor sotorasib. However, most of current

covalent drug discovery efforts are directed toward cysteines, which is the least abundant amino acid in the proteome (2%). Meanwhile, about 6% of mutants in cancer lead to serines. While some of these mutations directly contribute to oncogenic signaling (e.g. KRAS G12S), others confer clinical resistance to existing drugs

(e.g. EGFR C797S, BTK C481S). To date, direct engagement of these mutant serines have not be achieved. Methods to selectively engage amino acids beyond cysteine are highly desirable, as they will bridge the gap between the prevalence of serine-acquiring mutations in human cancer and the lack of chemical tools to target

them. This project aims to develop new chemistry that enables the covalent engagement of serine residues, especially those acquired in cancer such as EGFR(C797S) (Aim 1) and BTK C481S (Aim 2). Successful targeting of these proteins will provide new avenues for targeted cancer therapy. The chemistry developed in

this project will also serve as a platform for the discovery of new covalent ligands for currently “undruggable” cancer targets (Aim 3).