New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design

Abstract

Covalent inhibitors are experiencing a growing resurgence in drug design and are an increasingly useful tool in molecular biology. The ability to attach inhibitors to their targets by a covalent linkage offers pharmacodynamic and pharmacokinetic advantages, but this can also be a liability if undesired off-target reactions are not mitigated. The discovery of new electrophilic groups that react selectively with specific amino acid residues is therefore highly desirable in the design of targeted covalent inhibitors (TCIs). Additionally, the ability to control the reactivity through exploitation of the target enzyme's machinery, as in mechanism-based inhibitors (MBIs), greatly benefits from the discovery of new strategies. This Perspective showcases recent advances in electrophile development and their application in TCIs and MBIs, exhibiting high selectivity for their targets.

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mproinhibitor

“…Fig 1), on a subset of kinases from our database, showing an increase in the number of structures that can be covalentized. New covalent 'warheads', including reversible covalent warheads, such as cyanoacrylamides 60 , and clorofluoroacetamides 61 become available, both for cysteine residues 62 , but also for other amino acids [63][64][65] . These can be incorporated with little effort into the covalentizer pipeline.…”

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases

“…and methionine (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). There are more than 50 covalent FDA-approved drugs, and most react at amino acids other than cysteine, such as penicillin, which uses a β-lactam reactive group to form a covalent bond with a serine residue of the penicillin-binding protein target (42), and the oncology drug bortezomib, which uses a boronic acid warhead to react at a threonine residue on the proteasome (43).…”

“…There are more than 50 covalent FDA-approved drugs, and most react at amino acids other than cysteine, such as penicillin, which uses a β-lactam reactive group to form a covalent bond with a serine residue of the penicillin-binding protein target (42), and the oncology drug bortezomib, which uses a boronic acid warhead to react at a threonine residue on the proteasome (43). Historically most Food and Drug Administration (FDA)-approved covalent inhibitors fall into the category of mechanism-based inhibitors, which correspond to compounds that form a covalent bond with an enzyme active-site catalytic residue (44), or targeted covalent inhibitors, which form a covalent bond with bystander or noncatalytic residues (29). Most of the recently approved covalent inhibitors, such as ibrutinib or afatinib, along with investigational compounds like the K-Ras inhibitors AMG 510, MRTX849, and ARS-3248, are targeted covalent inhibitors that form a covalent bond at bystander cysteine residues.…”

Covalent Small Molecules as Enabling Platforms for Drug Discovery

“…This revival is the result of a better understanding of the factors governing the binding of these compounds, with a current emphasis aimed at optimising the noncovalent recognition to the biological target and employing tempered electrophiles to decrease, overall, the risks of off‐target reactivity. Excellent reports have recently reviewed the latest strategies available to research scientists to successfully produce covalent drug candidates . This review will not recapitulate these concepts but, instead, will focus on highlighting recent advances of covalent chemistry aimed at enabling small molecule drug discovery programmes.…”