Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation.

ABSTRACT: A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized via the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC₅₀ values against PI3Kδ, along with low micromolar to submicromolar GI₅₀ values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC₅₀ = 6.3 nM) and anti-proliferative activity (GI₅₀ = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, in vitro metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, a

SUBMITTER: Ma X 

PROVIDER: S-EPMC6431952 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature