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

• Main Authors: Samar A. El-Kalyoubi (Author), Hesham A. M. Gomaa (Author), Elshimaa M. N. Abdelhafez (Author), Mohamed Ramadan (Author), Fatimah Agili (Author), Bahaa G. M. Youssif (Author)
• Format: Book
• Published: MDPI AG, 2023-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <b>5a</b>, <b>5e</b>, and <b>7e</b> 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 <b>5a</b>, <b>5e</b>, and <b>7e</b> 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.

Item Description

10.3390/ph16050716
1424-8247