Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor
Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor
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(S)-2-氨基-N-(5-(6-氯-5-(3-甲基苯基磺酰胺基)吡啶-3-基)-4-甲基噻唑-2-基)-3-甲基丁酰胺(CHMFL-)的发现
DOI：
10.1016/j.ejmech.2018.07.036
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发表时间：
2018-08-05
影响因子：
6.7
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Liang, Xiaofei;Li, Feng;Liu, Jing
PI 3 K δ主要表达于白细胞，在B细胞受体介导的信号转导通路中起着重要作用，是治疗急性髓细胞白血病、慢性淋巴细胞白血病等B细胞恶性肿瘤的药物靶点。其中，化合物151（CHMFL-PI 3 K δ-317）在ADP-Glo生物化学测定中显示出6 nM的针对PI 3 K δ的IC 50。它还表现出超过其他I、II和III类PIKK家族同种型10-1500倍的选择性。此外，在细胞环境中，15 i可以选择性地和有效地抑制PI 3 K δ介导的Akt T308磷酸化，但不抑制PI 3 K δ、β、γ介导的Akt磷酸化。15 i在1 μ M浓度下对包括468种激酶/突变体的蛋白激酶也表现出极好的选择性。15 i具有可接受的药代动力学性质，并且可以剂量依赖性地抑制AML细胞系MOLM 14接种的异种移植小鼠模型的肿瘤生长。高选择性和效力使15 i成为当前PI 3 K delta军械库的潜在有价值的补充。(C)2018年Elsevier Masson SAS。All rights reserved.
PI3K delta, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3K delta inhibitors. Among them compound 151 (CHMFL-PI3K delta-317) displays an IC50 of 6 nM against PI3K delta in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3K delta mediated phosphorylation of Akt T308 but not PI3K delta, beta, gamma mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 mu M. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3K delta armory. (C) 2018 Elsevier Masson SAS. All rights reserved.