Therapeutic potential of anticancer activity of nitrogen-containing heterocyclic scaffolds as Janus kinase (JAK) inhibitor: Biological activity, selectivity, and structure–activity relationship

• Published in: Bioorganic chemistry Vol. 152; p. 107696
• Main Authors: Pal, Rohit, Matada, Gurubasavaraja Swamy Purawarga, Teli, Ghanshyam, Saha, Moumita, Patel, Rajiv
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; JAK inhibitor; JAK-STAT; Janus Kinase Inhibitors - chemical synthesis; Janus Kinase Inhibitors - chemistry; Janus Kinase Inhibitors - pharmacology; Janus Kinases - antagonists & inhibitors; Janus Kinases - metabolism; Molecular Structure; N-heterocyclic compounds; Neoplasms - drug therapy; Nitrogen - chemistry; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; SAR; Structure-Activity Relationship; JAK inhibitor; N-heterocyclic compounds; JAK-STAT; SAR; Cancer
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107696

[Display omitted] •The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors.•Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer.•N-heterocyclic ring has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics.•Medicinal chemistry perspective in terms of N-heterocyclic compounds, bioactivity, selectivity, and structure–activity relationships (SAR) is discussed. The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure–activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.