发现一种有效且选择性强的PI3Kγ/δ双重抑制剂，它是一种吡唑并[1,5-a]嘧啶衍生物。
Discovery of Pyrazolo[1,5-a]pyrimidine derivative as a potent and selective PI3Kγ/δ dual inhibitor.
发表日期：2023 Sep 01
作者：
Xiaofei Liang, Maoqing Deng, Fengming Zou, Ziping Qi, Chun Wang, Juan Liu, Qingwang Liu, Beilei Wang, Shuang Qi, Juan Ge, Hongwei Yu, Aoli Wang, Qingsong Liu, Jing Liu
来源：
Cellular & Molecular Immunology
摘要：
磷脂酰肌醇3激酶（PI3Kγ和δ）主要在白细胞中表达，并在调节免疫系统中发挥重要作用。双重抑制PI3Kγ/δ已成为调控肿瘤微环境的有效方法。本研究报告了结构活性关系优化的探索，发现了一种具有强效PI3Kγ/δ双重抑制活性的化合物15u（IHMT-PI3K-455）。在生化和细胞实验中，15u表现出良好的抑制活性，并能够将THP-1和BMDM巨噬细胞的M2表型重新极化为M1表型。此外，通过大鼠药物代谢动力学研究和MC38异种移植模型中的药效学研究，表明15u具有适当的体内药物性质。版权所有 © 2023 Elsevier Masson SAS。保留所有权利。
Phosphoinositol 3-kinases (PI3Ks) γ and δ are primarily expressed in leukocytes and play crucial roles in regulation of the immune system. Dual inhibition of PI3Kγ/δ has emerged as an effective approach to regulate the tumor microenvironment. Here, we report the exploration of structure-activity relationship optimization which led to the discovery of a potent PI3Kγ/δ dual inhibitor 15u (IHMT-PI3K-455). 15u exhibits strong potency in biochemical and cellular assays and it repolarizes M2 phenotype toward M1 phenotype in THP-1 and BMDM macrophages. In addition, it shows suitable in vivo properties as demonstrated through pharmacokinetic studies in rats and pharmacodynamics properties in a MC38 xenograft model.Copyright © 2023 Elsevier Masson SAS. All rights reserved.