Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets

Abstract

Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously “undruggable” proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical needs that covalent inhibitors have not yet addressed. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted covalent inhibitors (TCIs), and expanded TCIs. By reviewing both Food and Drug Administration (FDA)-approved drugs and drug candidates from recent literature, we provide insight into the future direction of covalent inhibitor development.

Machine learning-based integration develops multi regulated cell death-related signatures for improving outcomes and immune response in acute myeloid leukemia

“…Temozolomide [48] is lower IC50 score in subtype 2, and PCI − 34051 [49], Carmustine [50], KRAS (G12C) Inhibitor-12 [51] is higher IC50 score in subtype2. KRAS (G12C) Inhibitor-12 [51] is higher IC50 score in subtype2.…”

“…Temozolomide [48] is lower IC50 score in subtype 2, and PCI − 34051 [49], Carmustine [50], KRAS (G12C) Inhibitor-12 [51] is higher IC50 score in subtype2. KRAS (G12C) Inhibitor-12 [51] is higher IC50 score in subtype2. The uoropyrimidine 5-uorouracil (5-FU) is an antimetabolite drug that is widely used for the treatment of cancer [52,53].…”

An Innovative Approach to Address Neurodegenerative Diseases through Kinase-Targeted Therapies: Potential for Designing Covalent Inhibitors

“…This approach helps to mitigate some of the potential drawbacks associated with the formation of irreversible covalent adducts, but, at the same time, makes it more challenging to identify the proteins bound by these inhibitors. The most prevalent type of covalent inhibitor exhibiting reversible inhibition is named after this category because the term "reversible" accurately describes the underlying chemical mechanism [18]. In general, covalent inhibitors can be broadly classified into two categories based on whether the inhibition is reversible or irreversible upon dialysis, competition with excess substrate, or extended incubation times.…”

“…Both AD and PD are progressive diseases associated with the intracellular accumulation of toxic protein aggregates. Despite their distinct and evident phenotypic characteristics, they share a common etiology at the subcellular level [ 18 , 19 ]. However, the current treatment approaches for neurodegenerative diseases only target a small subset of the population and primarily focus on providing symptomatic relief, lacking the ability to alter the progression of the diseases [ 5 , 19 ].…”

“…Using a covalent kinase inhibitors (CKI) strategy in the design of new kinase inhibitors presents a compelling and innovative solution to address these challenges. CKI have been developed and reported as promising drug candidates for various diseases, with a particular emphasis on their therapeutic applications in the field of oncology [ 18 , 19 ]. Therefore, it is advisable to develop novel CKI-targeting kinases for which only anticancer inhibitors had been previously documented, for example, JNK3 (c-Jun N-terminal kinase 3).…”