Development of chemical platforms to deliver latent electrophiles

Abstract

Covalent drugs have seen a considerable resurgence in the last two decades. Till date, there are at least 50 FDA-approved drugs that act as covalent inhibitors with 14 approvals in the last decade itself. Even with the growing pool of covalent drugs in the market, there are several concerns credited to non-selective mode of action of covalent drugs. Covalent drugs have historically been ascribed to exert long lasting idiosyncratic effects exemplified by the presence of active covalently binding metabolites in the host. Consequently, covalent reactivity makes it paramount to reduce off-target reactivity while retaining efficacy towards the drug target in situ. To this end, more recently developed Targeted Covalent Inhibitors (TCIs) target non-catalytic residues which are poorly conserved across the target protein family. Thereby, such inhibitors provide a distinct selectivity profile compared to traditional reversible non-covalent drugs. With this background, work on the development of small molecule scaffolds in the bid to control the covalent reactivity of the electrophilic warhead groups was taken up in this thesis. Such warheads are critical in the design of TCIs. Herein, the design, synthesis and evaluation of small molecules equipped with masked electrophile functionalities is shown. The driving principle is that the compounds require to be exposed to certain stimuli before the electrophile becomes available to react with a nucleophilic residue of interest. This approach is expected to increase selectivity towards the target cells – cancer for example. Here, a description of release profiles of α, β- unsaturated electrophilic compounds relevant in the context of recently approved FDA-approved covalent drugs is provided.