A Review on Renaissance of Targeted Covalent Inhibitors

Review Article

Abstract

Targeted Covalent Inhibitors (TCIs) have evolved from their historical classification as non-selective toxins to become a cornerstone of modern precision medicine. While early pharmaceutical strategies largely avoided covalent modalities due to apprehensions regarding idiosyncratic toxicity and haptenization, the clinical success of third-generation kinase inhibitors and KRAS G12C modulators has catalyzed a paradigm shift in rational drug design. This resurgence is not merely a return to reactive chemistry but represents a sophisticated evolution towards tunable reversibility and the engagement of "difficult" nucleophiles. The integration of structural biology with reactive group chemistry now permits the targeting of residues previously considered undruggable, such as lysine, tyrosine, and serine, thereby vastly expanding the ligandable proteome. Current research prioritizes the decoupling of biochemical potency from systemic exposure through the optimization of residence time and the "hit-and-run" pharmacological profile. Furthermore, the development of reversible covalent warheads utilizing cyanoacrylates and aldehydesoffers a strategic solution to the challenges of permanent protein modification, mitigating off-target risks while maintaining high affinity. This review discusses about the trajectory of warhead evolution, the kinetic principles governing specific inactivation efficiency (k_inact/K_I), and the structural activity relationships that facilitate the precise modification of non-catalytic residues. The strategic deployment of these advanced chemical tools enables the effective interrogation of biological targets that are resistant to traditional non-covalent inhibition.