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Conformationally restricted quinazolone derivatives as PI3K?-selective inhibitors: the design, synthesis and biological evaluation.

ABSTRACT: A series of structurally novel quinazolone-based PI3K?-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 PI3K?, along with low micromolar to submicromolar GI50 values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3K? inhibitory activity (IC50 = 6.3 nM) and anti-proliferative activity (GI50 = 0.21 ?M) in this series, was further evaluated for its PI3K? 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, as a promising lead, merits extensive structural optimization for exploring novel PI3K?-selective inhibitors as clinical candidates.

SUBMITTER: Ma X

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

REPOSITORIES: biostudies-literature

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

Ma Xiaodong X Fang Fang F Tao Qiangqiang Q Shen Li L Zhong Guochen G Qiao Tao T Lv Xiaoqing X Li Jiaming J

MedChemComm 20190123 3

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-proliferat ...[more]

PMID: 30996859

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