3区 · 医学
Article
作者: Chan, Bryan K. ; Seward, Eileen ; Lainchbury, Michael ; Brewer, Thomas F. ; An, Le ; Blench, Toby ; Cartwright, Matthew W. ; Yan Chan, Grace Ka ; 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.
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.