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

Abstract

New 1H-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 in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC₅₀ values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFR^WT). Compound 12b was the most potent member showing an IC₅₀ value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFR^T790M) (IC₅₀ = 0.236 µM). Flow cytometric analyses revealed that compound 12b 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.

Graphical Abstract

Keywords:

• Anti-proliferative
• apoptosis
• EGFR inhibitors
• molecular docking
• 1H-pyrazolo[3,4-d]pyrimidine

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This paper is based upon work supported by Science, Technology & Innovation Funding Authority (STIFA) under grant number 43327.