Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).
Bryan K ChanEileen SewardMichael LainchburyThomas F BrewerLe AnToby BlenchMatthew W CartwrightGrace Ka Yan ChanEdna F ChooJason DrummondRichard L ElliottEmanuela GanciaLewis GazzardBaihua HuGraham E JonesXifeng LuoAndrew MadinSushant MalhotraJohn G MoffatJodie PangLaurent SalphatiChristopher J SneeringerCraig E StivalaBinqing WeiWeiru WangPing WuTimothy P HeffronPublished in: ACS medicinal chemistry letters (2021)
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.