Hematopoietic Progenitor Kinase 1 (HPK1) acts as a negative regulator of T-cell receptor mediated T-cell activation, and HPK1 has also been shown to play a negative regulatory role in many steps of the cancer-immunity cycle.  HPK1 kinase activity has been shown to be important in limiting T-cell receptor signaling and subsequent cytokine production using HPK1 kinase-dead knock-in mouse models.  Additionally, a sarcoma xenograft model in syngeneic HPK1 wild-type and kinase-dead mice demonstrated that loss of HPK1 kinase activity led to tumor suppression.  Thus, there is strong motivation to pursue small-molecule HPK1 inhibitors as potential cancer immunotherapies.  Our team pursued lead-optimization efforts culminating in the identification of a potent, selective series of small-molecule HPK1 inhibitors.  This presentation will disclose our optimization of the solubility and pharmacokinetic properties of this series, ultimately leading to orally bioavailable compounds with acceptable predicted human pharmacokinetics.

Property-based lead optimization of orally bioavailable HPK1 inhibitors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.