Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors.

ABSTRACT:

Introduction

Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity.

Methods

In this study, we designed and synthesized a series of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency.

Results and discussion

Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC₅₀: 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC₅₀: 44.6 ± 3.6 nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC₅₀: 15.4 ± 1.9 nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furt

SUBMITTER: Huang D 

PROVIDER: S-EPMC11533140 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature