Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold

In our study compounds with pyrido[3,2- ]pyrimidine and pyrido[3,4- ]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-...

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Bibliographic Details
Published in:Future medicinal chemistry 2023-08, Vol.15 (16), p.1491-1509
Main Authors: Ma, Mengyan, Feng, Yifan, Zhang, San-Qi, Duan, Weiming, Gao, Li, Yuan, Bo, Xin, Minhang
Format: Article
Language:English
Subjects:
novel pyridopyrimidine scaffold
PI3Kδ inhibitors
potent
pyrido[3,2
pyrimidine
selectivity
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Summary:In our study compounds with pyrido[3,2- ]pyrimidine and pyrido[3,4- ]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blotting and flow cytometry, respectively. Compounds , and containing pyrido[3,2- ]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) at subnanomolar levels and had good δ-isoform selectivity. , and showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in a good concentration-dependent manner. induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that , and bound tightly to PI3Kδ through key hydrogen bonding interactions. This study suggests that employing pyrido[3,2- ]pyrimidine can facilitate the design of novel potent and selective PI3Kδ inhibitors.
ISSN:1756-8919
1756-8927
DOI:10.4155/fmc-2023-0149