Covalent inhibitors: an opportunity for rational target selectivity

Abstract

There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine's thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine's amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[264] Therefore, the design of targeted covalent modifiers relies on the use of "warheads" with well-balanced reactivity,w hich is revealed only in close proximity to the targetb inding center after appropriate positioning of the ligand provided by noncovalent interactions. [253,264,265] Because typical covalenti nhibitors address nucleophilic side chains of cysteineo rserine/threonine (less common cases include reactions with lysine, [266] histidine, methionine, or tyrosine residues [253] ), the list of most populari rreversible covalent warheadsi ncludes electrophilicm oieties, [253,261] such as Michael acceptors (a,b-unsaturated carbonyl compounds, acrylamides, vinyl sulfones, vinyl sulfonamides,e tc. ), compounds capable of formingS ÀSbonds (e.g.,thiols), sulfonyl fluorides, [267] epoxides, b-lactones and b-lactams, and alkylating agents.…”

How Reactive are Druggable Cysteines in Protein Kinases?

“…5 Recently, there has been renewed interest among medicinal chemists in developing kinase inhibitors that bind covalently to target proteins. [6][7][8][9][10][11][12][13][14] Targeted covalent inhibitors (TCIs) augment conventional noncovalent protein-ligand interactions with a covalent linkage with a side chain of the target. 6,8 As a result, TCIs can achieve greater binding affinity, a longer residence time, and a pro-longed duration of therapeutic action in comparison to their conventional noncovalent counterparts.…”

Targeting pharmacophore with probe‐reactivity‐guided fractionation to precisely identify electrophilic sesquiterpenes and its activity of anti‐TNBC

“…Application of ES compounds to TNBC treatment shows promising prospects . These ESs may exercise their biological activities by reacting with an appropriately positioned nucleophilic residue available on targeted proteins or enzymes (usually, but not always, a cysteine thiol amino acid group) . Thiol groups plays an important role in TNBC‐related pathways and physiology.…”

“…[7][8][9] These ESs may exercise their biological activities by reacting with an appropriately positioned nucleophilic residue available on targeted proteins or enzymes (usually, but not always, a cysteine thiol amino acid group). 6,7,[10][11][12] Thiol groups plays an important role in TNBC-related pathways and physiology. For example, 17-hydroxy-jolkinolide B reacts with cystein residues of Janus kinase (JAK) inhibitors to form covalent bonds that inhibit constitutive activation of the JAK/STAT3 pathway, thus preventing TNBC oncogenesis.…”