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Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

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Towards optimization of the pyrrolizine-5-carboxamide scaffold, a novel series of six derivatives (4a-c and 5a-c) was prepared and evaluated for their anti-inflammatory, analgesic and anticancer activities. The (EZ)-7-cyano-6-((4-hydroxybenzylidene)amino)-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4b) and (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5b) bearing the electron donating methyl group showed the highest anti-inflammatory activity while (EZ)-6-((4-chlorobenzylidene)amino)-7-cyano-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5a) was the most active analgesic agent. Cytotoxicity of the new compounds was evaluated against the MCF-7, A2780 and HT29 cancer cell lines using the MTT assay. Compounds 4b and 5b displayed high anticancer activity with IC50 in the range of 0.30–0.92 μmol L−1 against the three cell lines, while compound (EZ)-N-(4-chlorophenyl)-7-cyano-6-((4-hydroxybenzylidene)-amino)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4c) was the most active against MCF-7 cells (IC50 = 0.08 μmol L−1). Both the anti-inflammatory and anticancer activities of the new compounds were dependent on the type of substituent on the phenyl rings. Substituents with opposite electronic effects on the two phenyl rings are preferable for high cytotoxicity against the MCF-7 and A2780 cells. COX inhibition was suggested as the molecular mechanism of the anti-inflammatory activity of the new compounds while no clear relationship could be observed between COX inhibition and anticancer activity. Compound 5b, the most active against the three cell lines, induced dose-dependent early apoptosis with 0.1–0.2 % necrosis in MCF-7 cells. New compounds showed promising drug-likeness scores while the docking study revealed high binding affinity to COX-2. Taken together, this study highlighted the significant impact of the substituents on the anti-inflammatory and anticancer activity of pyrrolizine-5-carboxamides, which could help in further optimization to discover good leads for the treatment of cancer and inflammation.