Discovery of new 1 <i>H</i> -pyrazolo[3,4- <i>d</i> ]pyrimidine derivatives as anticancer agents targeting EGFR ^WT and EGFR ^T790M

Abstract

New 1<i>H</i>-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their <i>in vitro</i> anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds <b>8, 10, 12a,</b> and <b>12b</b> showed potent anti-proliferative activities. Compound <b>12b</b> was the most promising member with IC₅₀ values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds <b>8, 10, 12a,</b> and <b>12b</b> were evaluated for their kinase inhibitory activities against wild EGFR (EGFR^WT). Compound <b>12b</b> was the most potent member showing an IC₅₀ value of 0.016 µM. In addition, compound <b>12b</b> showed noticeable activity against mutant EGFR (EGFR^T790M) (IC₅₀ = 0.236 µM). Flow cytometric analyses revealed that compound <b>12b</b> is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFR^WT and EGFR^T790M.