Discovery of new 1 H-pyrazolo[3,4- d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M

Ahmed A Gaber; Mohamed Sobhy; Abdallah Turky; Hanan Gaber Abdulwahab; Ahmed A Al-Karmalawy; Mostafa A Elhendawy; Mohamed M Radwan; Eslam B Elkaeed; Ibrahim M Ibrahim; Heba S A Elzahabi; Ibrahim H Eissa

doi:10.1080/14756366.2022.2112575

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2283-2303. doi: 10.1080/14756366.2022.2112575.

Authors

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
³ Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.
⁴ Department of Chemistry and Biochemistry, University of Mississippi, MS, USA.
⁵ Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt.
⁶ National Center for Natural Products Research, University of Mississippi, University, MS, USA.
⁷ Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
⁸ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁹ Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt.
¹⁰ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

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.

Keywords: 1H-pyrazolo[3,4-d]pyrimidine; Anti-proliferative; EGFR inhibitors; apoptosis; molecular docking.

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
ErbB Receptors / metabolism
Humans
Lung Neoplasms* / drug therapy
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyrimidines / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
EGFR protein, human
ErbB Receptors

Grants and funding

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