Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics

Abstract

Covalent inhibitors have been used to treat several diseases for over a century. However, strategic approaches for the rational design of covalent drugs have taken a definitive shape in recent times. Since the first appearance of covalent inhibitors in the late 18th century, the field has grown tremendously and around 30% of marketed drugs are covalent inhibitors especially, for oncology indications. However, the off‐target toxicity and safety concerns can be significant issues related to the covalent drugs. Covalent kinase inhibitor (CKI) targeted oncotherapeutics has advanced dramatically over the last two decades since the discovery of afatinib (Gilotrif®), an EGFR inhibitor. Since then, US FDA has approved 10 CKIs for diverse cancer targets. The present review broadly summarizes the ongoing development in the discovery of newer CKIs from 2016 till the end of 2022. We believe that these efforts will assist the modern medicinal chemist actively working in the field of CKI discovery for varied indications.

An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

“…As a result, the design of target-specific covalent inhibitors has been intensified, also including efforts to minimize the chance of unwanted side effects. In fact, however, the majority of the drugs approved by the FDA are equipped with warheads exerting promiscuous reactivity [ 83 , 84 , 85 , 86 , 87 ]. But recent reports have clarified that the optimized choice of appropriate noncovalent interactions, which play a crucial role in molecular recognition (as provided by the main scaffold of the warhead compound), combined with the distinctly linked warhead moiety (providing the covalent linkage property), have matched the drug reactivity with specific residues, thus reducing the chance of off-target labeling, even in the case of the promiscuous warheads.…”

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

“…Irreversible covalent binding can enhance drug selectivity, which can aid in the development of selective inhibitors and overcoming resistance [48,49]. However, irreversible kinase binding has introduced new challenges, including increased side effects, unpredictable toxicity, and immunogenicity from covalent complexes [50][51][52]. Despite the effectiveness of second-generation EGFR inhibitors like afatinib and dacomitinib, they also inhibit the wild-type EGFR, leading to severe side effects.…”