Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3K alpha between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.

Automated summary

This study focuses on the synthesis, enzymatic activities, in silico docking, and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines on PI3K and mTOR. By altering the substituents at the C-7 position, compounds with improved kinase efficiency were identified, with some showing promising activity on PI3K alpha. The most effective compounds induced micromolar cytotoxicity on cancer cell lines with overactivated PI3K pathway.