Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Huanrong Bai; Jiajia Sun; Hao Lei; San Qi Zhang; Bo Yuan; Mengyan Ma; Minhang Xin

doi:10.1002/ddr.22114

Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Huanrong Bai
, Jiajia Sun
, Hao Lei
, San Qi Zhang
, Bo Yuan
, Mengyan Ma
, Minhang Xin

Health Science Center

Xi'an Jiaotong University

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC₅₀ = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC₅₀ = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

Original language	English
Pages (from-to)	1709-1723
Number of pages	15
Journal	Drug Development Research
Volume	84
Issue number	8
DOIs	https://doi.org/10.1002/ddr.22114
State	Published - Dec 2023

Keywords

PI3Kδ inhibitors
antiproliferation
hematologic malignancies
pyrido[3,2-d]pyrimidine
selectivity

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10.1002/ddr.22114

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title = "Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors",

abstract = "The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.",

keywords = "PI3Kδ inhibitors, antiproliferation, hematologic malignancies, pyrido[3,2-d]pyrimidine, selectivity",

author = "Huanrong Bai and Jiajia Sun and Hao Lei and Zhang, \{San Qi\} and Bo Yuan and Mengyan Ma and Minhang Xin",

note = "Publisher Copyright: {\textcopyright} 2023 Wiley Periodicals LLC.",

year = "2023",

month = dec,

doi = "10.1002/ddr.22114",

language = "英语",

volume = "84",

pages = "1709--1723",

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TY - JOUR

T1 - Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

AU - Bai, Huanrong

AU - Sun, Jiajia

AU - Lei, Hao

AU - Zhang, San Qi

AU - Yuan, Bo

AU - Ma, Mengyan

AU - Xin, Minhang

PY - 2023/12

Y1 - 2023/12

N2 - The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

AB - The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

KW - PI3Kδ inhibitors

KW - antiproliferation

KW - hematologic malignancies

KW - pyrido[3,2-d]pyrimidine

KW - selectivity

UR - https://www.scopus.com/pages/publications/85171631780

U2 - 10.1002/ddr.22114

DO - 10.1002/ddr.22114

M3 - 文章

C2 - 37732677

AN - SCOPUS:85171631780

SN - 0272-4391

VL - 84

SP - 1709

EP - 1723

JO - Drug Development Research

JF - Drug Development Research

IS - 8

ER -

Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Abstract

Keywords

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