Design, Synthesis, and Anti-Proliferative Action of Purine/Pteridine-Based Derivatives as Dual Inhibitors of EGFR and BRAFV600E

Samar A El-Kalyoubi; Hesham A M Gomaa; Elshimaa M N Abdelhafez; Mohamed Ramadan; Fatimah Agili; Bahaa G M Youssif

doi:10.3390/ph16050716

Design, Synthesis, and Anti-Proliferative Action of Purine/Pteridine-Based Derivatives as Dual Inhibitors of EGFR and BRAF^V600E

Pharmaceuticals (Basel). 2023 May 8;16(5):716. doi: 10.3390/ph16050716.

Authors

Samar A El-Kalyoubi¹, Hesham A M Gomaa², Elshimaa M N Abdelhafez³, Mohamed Ramadan⁴, Fatimah Agili⁵, Bahaa G M Youssif⁶

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42511, Egypt.
² Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia.
³ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
⁴ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 11651, Egypt.
⁵ Chemistry Department, Faculty of Science (Female Section), Jazan University, Jazan 82621, Jazan, Saudi Arabia.
⁶ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.

Abstract

The investigation of novel EGFR and BRAF^V600E dual inhibitors is intended to serve as targeted cancer treatment. Two sets of purine/pteridine-based derivatives were designed and synthesized as EGFR/BRAF^V600E dual inhibitors. The majority of the compounds exhibited promising antiproliferative activity on the cancer cell lines tested. Compounds 5a, 5e, and 7e of purine-based and pteridine-based scaffolds were identified as the most potent hits in anti-proliferative screening, with GI₅₀ values of 38 nM, 46 nM, and 44 nM, respectively. Compounds 5a, 5e, and 7e demonstrated promising EGFR inhibitory activity, with IC₅₀ values of 87 nM, 98 nM, and 92 nM, respectively, when compared to erlotinib's IC₅₀ value of 80 nM. According to the results of the BRAF^V600E inhibitory assay, BRAF^V600E may not be a viable target for this class of organic compounds. Finally, molecular docking studies were carried out at the EGFR and BRAF^V600E active sites to suggest possible binding modes.

Keywords: BRAF; EGFR; anti-proliferative; cancer; docking; pteridine; purine.

Grants and funding

This research received no external funding.