吲唑
化学
配体(生物化学)
离体
调节器
激酶
计算生物学
T细胞受体
细胞生物学
立体化学
生物化学
生物
T细胞
受体
体外
免疫系统
免疫学
基因
作者
Elsie C. Yu,Joey L. Methot,Xavier Fradera,Charles A. Lesburg,Brian M. Lacey,Phieng Siliphaivanh,Ping Liu,Dustin Smith,Zangwei Xu,Jennifer Piesvaux,Shuhei Kawamura,Haiyan Xu,J. Richard Miller,Mark Bittinger,Alexander Pasternak
标识
DOI:10.1021/acsmedchemlett.0c00672
摘要
Hematopoietic progenitor kinase (HPK1), a negative regulator of TCR-mediated T-cell activation, has been recognized as a novel antitumor immunotherapy target. Structural optimization of kinase inhibitor 4 through a systematic two-dimensional diversity screen of pyrazolopyridines led to the identification of potent and selective compounds. Crystallographic studies with HPK1 revealed a favorable water-mediated interaction with Asp155 and a salt bridge to Asp101 with optimized heterocyclic solvent fronts that were critical for enhanced potency and selectivity. Computational studies of model systems revealed differences in torsional profiles that allowed for these beneficial protein-ligand interactions. Further optimization of molecular properties led to identification of potent and selective reverse indazole inhibitor 36 that inhibited phosphorylation of adaptor protein SLP76 in human PBMC and exhibited low clearance with notable bioavailability in in vivo rat studies.
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