The Ascension of Targeted Covalent Inhibitors

Abstract

Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceutical industry over concerns about the potential for toxicity. A resurgence has occurred driven by the clinical success of targeted covalent inhibitors (TCIs), with eight drugs approved over the past decade. The opportunity to create unique drugs by exploiting the covalent mechanism of action has enabled clinically decisive target product profiles to be achieved. TCIs have revolutionized the treatment paradigm for non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight the clinical and financial success of this class of drugs and provide early insight into toxicity, a key factor that had hindered progress in the field. Further innovation in the TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, and cancer, highlights the broad opportunity to deliver a new generation of breakthrough therapies.

Systematic exploration of privileged warheads for covalent kinase drug discovery

“…Meanwhile, the distribution of non-conserved nucleophilic amino acids (such as cysteine) across the whole kinome increase specificity and hence selectivity of kinase inhibitors. 7,22,24,26,[28][29] In short, CKIs enrich selectivity over the whole kinome. Important since there are more than 200 kinases over the kinome with available cysteines and other nucleophiles 28 , which suggests there is plenty of room left for continued efforts to generate new covalent drugs 12 .…”

“…We collected all CKIs from recent scientific reviews 5,7,10,[24][25][26] and published databases including CovalentInDB 27 and ACS publications (https://www.acs.org). First, the ACS publications were searched using the query words "covalent or irreversible" and "kinase" and "inhibitors."…”

“…There are eight CKIs that have been approved by the FDA (Figure 1) and more than 300 are in clinical trials. 11,26 Different amino acid side chains, such as lysine, cysteine, aspartic acid, and tyrosine, are used as nucleophilic groups.…”

PROTAC degraders as chemical probes for studying target biology and target validation

“…Covalent and reversible-covalent targeting represent inhibitor design strategies that have become increasingly popular in particular in kinase drug discovery, where targeting of cysteine residues led to the discovery of inhibitors and drugs with increased selectivity and efficacy. [88][89][90] However, the development of covalent PROTAC chemical probes requires additional characterization as kinetic parameter of bond formation need to be considered and covalent binding in cellular environments should be confirmed. An advantage of covalent inhibitors is that the activity of an irreversible covalently modified target returns only after the target has been re-expressed.…”

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

“…Targeted covalent inhibition (TCI), wherein a reactive group (warhead) is strategically incorporated onto a reversible ligand of the target protein to facilitate specific covalent engagement, is being increasingly recognized as a powerful concept for drug discovery. [61] Vinyl sulfones and sulfonamides have been often utilized as warheads for covalent inhibition. [62] Given the prior examples of the successful replacement of sulfones and sulfonamides for sulfoximines in the discovery of reversible inhibitors (vide supra), it seems obvious to evaluate vinyl sulfoximines for covalent inhibition, too.…”