The success of drugs such as ibrutinib and osimertinib has led to renewed interest in irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic amino acids. Irreversible inhibitors have several potential advantages including high potency and specificity, and prolonged pharmacodynamics. Despite significant effort, the simple acrylamide Michael acceptor remains ‘state of the art’ in terms of cysteine capture, due to its ease of synthesis, acceptable reactivity window and DMPK compatibility. Acrylamide reactivity is greatly influenced by the nature of its connection to the non-covalent binding element of such potential drugs, which in turn, is dictated by the SAR for binding to the chosen target. Therefore, there remains a significant need for additional cysteine reactive warheads with tuneable properties and reactivity profiles which present attachment vectors not accessible with acrylamides.<br/>We report here our work on the synthesis, reactivity and application of novel vinyl- and alkynyl-substituted heterocycles (both aromatic and non-aromatic) as alternative electrophilic warheads for chemical biological probes and drug molecules. These heterocycles are capable of covalent bond formation with cysteines and present novel binding and attachment vectors. Exploration of electronic and steric effects on varying scaffolds has revealed unique reactivity profiles, differentiating the novel heterocycles further from the traditional acrylamide motif. Moreover, we have demonstrated that suitable examples of these novel covalent binding warheads can be incorporated into known drug scaffolds, retaining potency and good pharmacological properties.<br/>Additionally, current effort is directed towards application of these new warheads to target previously ‘undruggable’ cysteines and extend the scope of current covalent cysteine targeting.<br/>

Design, synthesis, and evaluation of novel heterocyclic warheads for cysteine targeting covalent inhibitors

2019 Fall National Meeting

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