posted on 2021-02-19, 13:06authored byAndrew P. Degnan, Godwin K. Kumi, Christopher W. Allard, Erika V. Araujo, Walter L. Johnson, Kurt Zimmermann, Bradley C. Pearce, Steven Sheriff, Alan Futran, Xin Li, Gregory A. Locke, Dan You, John Morrison, Karen E. Parrish, Caitlyn Stromko, Anwar Murtaza, Jinqi Liu, Benjamin M. Johnson, Gregory D. Vite, Mark D. Wittman
While the discovery of immune checkpoint
inhibitors has led to
robust, durable responses in a range of cancers, many patients do
not respond to currently available therapeutics. Therefore, an urgent
need exists to identify alternative mechanisms to augment the immune-mediated
clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a
serine-threonine kinase that acts as a negative regulator of T-cell
receptor (TCR) signaling, to dampen the immune response. Herein we
describe the structure-based discovery of isofuranones as inhibitors
of HPK1. Optimization of the chemotype led to improvements in potency,
selectivity, plasma protein binding, and metabolic stability, culminating
in the identification of compound 24. Oral administration
of 24, in combination with an anti-PD1 antibody, demonstrated
robust enhancement of anti-PD1 efficacy in a syngeneic tumor model
of colorectal cancer.