139253-79-5Relevant articles and documents
Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1)
Chan, Bryan K.,Seward, Eileen,Lainchbury, Michael,Brewer, Thomas F.,An, Le,Blench, Toby,Cartwright, Matthew W.,Chan, Grace Ka Yan,Choo, Edna F.,Drummond, Jason,Elliott, Richard L.,Gancia, Emanuela,Gazzard, Lewis,Hu, Baihua,Jones, Graham E.,Luo, Xifeng,Madin, Andrew,Malhotra, Sushant,Moffat, John G.,Pang, Jodie,Salphati, Laurent,Sneeringer, Christopher J.,Stivala, Craig E.,Wei, Binqing,Wang, Weiru,Wu, Ping,Heffron, Timothy P.
supporting information, p. 84 - 91 (2021/12/17)
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 in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.
MACROCYCLIC KINASE INHIBITORS
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Page/Page column 55, (2012/06/16)
Compounds of Formula (I): wherein variables are defined herein, and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers for which FAK inhibition is beneficial.
