7L24

HPK1 IN COMPLEX WITH COMPOUND 11

7L24 の概要

• エントリーDOI: 10.2210/pdb7l24/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 6-(2-fluoro-6-methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]pyridine (3 entities in total)
• 機能のキーワード: hpk1 hematopoietic progenitor kinase, inhibitor complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 131012.74

構造登録者

Lesburg, C.A. (登録日: 2020-12-16, 公開日: 2021-03-17, 最終更新日: 2024-04-03)

主引用文献

Yu, E.C.,Methot, J.L.,Fradera, X.,Lesburg, C.A.,Lacey, B.M.,Siliphaivanh, P.,Liu, P.,Smith, D.M.,Xu, Z.,Piesvaux, J.A.,Kawamura, S.,Xu, H.,Miller, J.R.,Bittinger, M.,Pasternak, A.
Identification of Potent Reverse Indazole Inhibitors for HPK1.
Acs Med.Chem.Lett., 12:459-466, 2021

PubMed Abstract: 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.

PubMed: 33738073
DOI: 10.1021/acsmedchemlett.0c00672

実験手法

X-RAY DIFFRACTION (2.68 Å)