Pyrazine-based small molecule kinase inhibitors: clinical applications and patent review (2019–2023)

Protein kinases play a key role in cellular signaling pathways including proliferation, apoptosis, inflammation and immune regulation. Therefore, targeting kinases with small molecules has emerged as a therapeutic potential in cancers and other diseases including inflammatory and autoimmune disorders. The main chemical motifs of the available small molecule kinase inhibitors are heterocyclic, nitrogen-containing and six-membered rings including pyrazine. Several potent and selective pyrazine-based kinase inhibitors have been developed and progressed into clinical trials. The data of clinical application of kinase inhibitors demonstrate good clinical activity with manageable toxicity in several relapse-resistant malignancies and severe to moderate immunological disorders. All pyrazine-based kinase inhibitors are orally active. This paper reviews the most recent kinase literature (2019–2023) related to pyrazine-based small molecule inhibitors. This review includes the FDA (Food and Drug Administration)-approved and patent agents along with their targeted kinase, scaffold, potency, selectivity profile, assignee and biological results in clinical and preclinical studies. The main chemical scaffolds of pyrazine-based small molecule inhibitors were imadazopyrazines, pyrazolopyrazines, triazolopyrazines, pyrazinopyrazines and 2-aminopyrazines. Various potent, selective and orally active pyrazine-based kinase inhibitors have been developed and progressed into clinical trials. The results of clinical applications of kinase inhibitors indicate clinical activity with manageable toxicity in a number of relapse-resistant malignancies, and severe to moderate immunological disorders. Most pyrazine-based kinase inhibitors act as ATP-competitive and bind to the ATP binding pocket of the active or inactive form of the enzyme, reversibly through hydrogen bonding and hydrophobic interactions or irreversible through covalent bonding. Resistance of malignant cells to kinase therapy is common and mainly due to mutation of the gatekeeper residue of the enzyme.