Yu Elsie C, Methot Joey L, Fradera Xavier, Lesburg Charles A, Lacey Brian M, Siliphaivanh Phieng, Liu Ping, Smith Dustin M, Xu Zangwei, Piesvaux Jennifer A, Kawamura Shuhei, Xu Haiyan, Miller J Richard, Bittinger Mark, Pasternak Alexander
Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, 02115, United States.
Computational and Structural Chemistry, Merck & Co., Inc., Boston, Massachusetts, 02115, United States.
ACS Med Chem Lett. 2021 Mar 1;12(3):459-466. doi: 10.1021/acsmedchemlett.0c00672. eCollection 2021 Mar 11.
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 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 that inhibited phosphorylation of adaptor protein SLP76 in human PBMC and exhibited low clearance with notable bioavailability in rat studies.
造血祖细胞激酶（HPK1）是TCR介导的T细胞活化的负调节因子，已被确认为一种新型的抗肿瘤免疫治疗靶点。通过对吡唑并吡啶进行系统的二维多样性筛选对激酶抑制剂进行结构优化，从而鉴定出强效且选择性的化合物。对HPK1进行的晶体学研究表明，其与Asp155形成了有利的水介导相互作用，并与Asp101形成了盐桥，同时优化的杂环溶剂前沿对增强效力和选择性至关重要。对模型系统的计算研究揭示了扭转轮廓的差异，这些差异促成了这些有益的蛋白质-配体相互作用。对分子性质的进一步优化导致鉴定出强效且选择性的反向吲唑抑制剂，该抑制剂可抑制人外周血单个核细胞中衔接蛋白SLP76的磷酸化，并且在大鼠研究中显示出低清除率和显著的生物利用度。
