Liang, Xiaofei; Li, Feng; Chen, Cheng; Jiang, Zongru; Wang, Aoli; Liu, Xiaochuan; Ge, Juan; Hu, Zhenquan; Yu, Kailin; Wang, Wenliang; Zou, Fengming; Liu, Qingwang; Wang, Beilei; Wang, Li; Zhang, Shanchun; Wang, Yuxin; Liu, Qingsong; Liu, Jing published the artcile< 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>, Category: esters-buliding-blocks, the main research area is phosphoinositide kinase delta PI3Kdelta inhibitor antitumor; Acute myeloid leukemia; Kinase inhibitor; PI3Kδ; Structure-activity relationship.
PI3Kδ, 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 pharmacol. evaluation of a novel series of aminothiazole-pyridine containing PI3Kδ inhibitors. Among them compound 15i (CHMFL-PI3KD-317) displays an IC50 of 6 nM against PI3Kδ in the ADP-Glo biochem. 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 PI3Kδ mediated phosphorylation of Akt T308 but not PI3Kα, β, γ mediated Akt phosphorylation. 15I also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 μM. 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 PI3Kδ armory.
European Journal of Medicinal Chemistry published new progress about Acute myeloid leukemia. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Category: esters-buliding-blocks.
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