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Int J Mol Sci. 2019 Nov 8;20(22). pii: E5592. doi: 10.3390/ijms20225592.

Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors.

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Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11284, Egypt.
Chemistry department, Faculty of Science, Taibah University, Medina 30002, Saudi Arabia.
Chemistry Department, Faculty of Science, Jazan University, Jazan 45142, Saudi Arabia.
Pharmacognosy Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt.
Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11284, Egypt.


Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4-33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 μM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.


anti-proliferative; extracellular signal-regulated kinases (ERK); pyrazole; pyrimidine; rational design; sulfonamides

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