7R9P

Crystal structure of HPK1 in complex with compound 14

Summary for 7R9P

• Entry DOI: 10.2210/pdb7r9p/pdb
• Descriptor: Hematopoietic progenitor kinase, 6-amino-2-fluoro-N,N-dimethyl-3-(4'-methylspiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-5'-yl)benzamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, map4k1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 67185.73

Authors

Wu, P.,Lehoux, I.,Wang, W. (deposition date: 2021-06-29, release date: 2022-01-05, Last modification date: 2023-10-18)

Primary citation

Chan, B.K.,Seward, E.,Lainchbury, M.,Brewer, T.F.,An, L.,Blench, T.,Cartwright, M.W.,Chan, G.K.Y.,Choo, E.F.,Drummond, J.,Elliott, R.L.,Gancia, E.,Gazzard, L.,Hu, B.,Jones, G.E.,Luo, X.,Madin, A.,Malhotra, S.,Moffat, J.G.,Pang, J.,Salphati, L.,Sneeringer, C.J.,Stivala, C.E.,Wei, B.,Wang, W.,Wu, P.,Heffron, T.P.
Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).
Acs Med.Chem.Lett., 13:84-91, 2022

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved ADME properties and the ability to induce cytokine production in primary human T-cells.

PubMed: 35059127
DOI: 10.1021/acsmedchemlett.1c00473

Experimental method

X-RAY DIFFRACTION (2.27 Å)