Protein Kinase Inhibitors in Drug Discovery

Abstract

Protein kinases (PKs) have essential roles in cell‐signaling pathways by interacting with extracellular ligands such as growth factors and hormones and transmitting signals across the cell membrane to the cytoplasm and the nucleus. It is important to understand the mechanistic features of the particular target kinase when designing protein kinase inhibitors (PKIs). This chapter focuses on inhibitors directed against critical molecular targets that are approved or are in clinical trials.

Dual Targeting of VEGFR2 and C-Met Kinases via the Design and Synthesis of Substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one Derivatives as Angiogenesis Inhibitors

“…The requisite Nsubstituted isatin 2 was prepared by alkylation from their Nunsubstituted analogues as reported 43−45 with bromoalkanes under anhydrous condition via stirring in dimethylformamide (DMF) or acetonitrile in the presence of K 2 CO 3 in room temperature overnight or under reflux. The synthesis of the requisite series of compounds 2-(6-aryl-7H- [1,2,4]triazolo [3,4b][1,3,4]thiadiazin-3-yl)hydrazin-1-ium chloride (5a−d) was conducted by the reflux of purpald (4; 4-amino-5-hydrazino-1,2,4-triazole-3-thiol) and phenacyl bromides (3) in the presence of hydrochloric acid (1 N). 46 The target compounds 6a−y were prepared by refluxing the intermediate 5 with isatin 2 in ethanol where the desired target product precipitates during the reaction, which is isolated by suction filtration, followed by recrystallization from aqueous DMF.…”

“…The main role of RTKs is to phosphorylate the tyrosine amino acid in several proteins aided by ATP (γ-phosphoryl group donor). 1 , 2 This phosphorylation activates the signaling pathway at the cellular level, which is a crucial process for differentiation, proliferation, migration, and antiapoptotic pathway. However, dysregulation of RTK signaling at the cellular level leads to an assortment of human diseases, most notably cancers.…”

“…Receptor tyrosine kinases (RTKs) are a large family of kinase enzymes targeted by different chemotherapeutic medications. The main role of RTKs is to phosphorylate the tyrosine amino acid in several proteins aided by ATP (γ-phosphoryl group donor). , This phosphorylation activates the signaling pathway at the cellular level, which is a crucial process for differentiation, proliferation, migration, and antiapoptotic pathway. However, dysregulation of RTK signaling at the cellular level leads to an assortment of human diseases, most notably cancers. , The vascular endothelial growth factor 2 (VEGFR2) and c-mesenchymal epithelial transition factor (c-Met) are RTKs which are linked to the hepatocyte growth factor and endothelial cells, respectively.…”

“…Such numerous reported studies for targeting VEGFR2 and c-Met-mediated tumorigenesis have drawn tremendous interest and prompt us to synthesize a series of hybrid 3-hydrazinoindolin-2-one derivatives (6a−y; Scheme 1). The synthesized compounds include two series of 3-hydrazino-indolin-2-one derivatives in which the terminal N is directly attached to the [1,2,4]triazolo [3,4-b][1,3,4]thiadiazine moiety. These compounds were investigated for their cytotoxic activity by the National Cancer Institute (NCI, USA) at 10 μM in a full NCI 58 cell panel.…”

Multimodal electrochemical and nanoplasmonic biosensors using ferrocene-crowned nanoparticles for kinase drug discovery applications

“…These have been applied for the detection of protein phosphorylation driven by kinases. Abnormal phosphorylation of proteins, interceded by kinases, is an important cellular regulation in several aspects of neoplasia [3]. Furthermore, there are over 400 diseases now linked either directly or indirectly to the activity of protein kinases [4][5][6][7].…”