Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFR and EGFR

• Published in: Organic & biomolecular chemistry 2020-10, Vol.18 (38), p.768-7634
• Main Authors: Nasser, Ahmed A, Eissa, Ibrahim H, Oun, Mohamed R, El-Zahabi, Mohamed A, Taghour, Mohammed S, Belal, Amany, Saleh, Abdulrahman M, Mehany, Ahmed B. M, Luesch, Hendrik, Mostafa, Ahmad E, Afifi, Wael M, Rocca, James R, Mahdy, Hazem A
• Format: Article
• Language: English
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d0ob01557a

A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11 a , 11 b , 12 b , 15 b and 16 a , were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11 b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC 50 values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC 50 values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFR WT and EGFR T790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11 b was also found to be the most active compound against both EGFR WT and mutant EGFR T790M , exhibiting IC 50 values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11 b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11 b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFR WT and EGFR T790M . Additional in silico ADMET studies were performed to explore drug-likeness properties. A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR).