7L24

HPK1 IN COMPLEX WITH COMPOUND 11

Summary for 7L24

• Entry DOI: 10.2210/pdb7l24/pdb
• Descriptor: 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)
• Functional Keywords: hpk1 hematopoietic progenitor kinase, inhibitor complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 131012.74

Authors

Lesburg, C.A. (deposition date: 2020-12-16, release date: 2021-03-17, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.68 Å)