Abstract 20: Targeting difficult targets with lysine-covalent ligands: Expanding the druggable space for covalent drugs

Abstract

Abstract Oncology drugs osimertinib, ibrutinib, neratinib, and afatinib have all been approved in very recent years by the FDA, and all target a cysteine that is present in proximity to the binding site of their respective targets. More recently, Amgen reported on AMG 510 as a first-in-class investigational drug designed to selectively and irreversibly target the KRAS G12C protein. These drugs rely on acrylamides moieties strategically incorporated in their chemical structures to selectively and efficiently react with binding site cysteine residues. Obviously, the approach is limited to drug targets that present a cysteine residue in proximity to the binding site, which often is not the case. This druggable target space for covalent drugs is called the Cysteinome. My laboratory has been developing and applying novel strategies aimed at deriving potent, selective, cell-permeable, and efficacious covalent therapeutics by designing agents that can selectively react with lysine residues (1,2). The approach relies on introducing stable aryl-fluorosulfates or sulfonyl-fluorides in drug leads to selectively and efficiently react with lysine residues. Because lysines are more ubiquitously found within the binding pocket of the target oncogenes, the approach defines a much larger target space for covalent drugs: the Lysinome. In addition, I will demonstrate that the approach is amenable also to tackle difficult targets such as those involving protein-protein interactions (PPIs). Hence, our work widens the available target space beyond cysteine and also allows the development of novel drug candidates against PPIs, which represent an untapped large class of therapeutic targets in oncology. Examples will include potent and selective Lys-covalent agents targeting antiapoptotic proteins in the IAP and Bcl-2 families of proteins, including particularly exciting, yet to be published results.