Design and Synthesis of Functionally Active 5‑Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1

Immune activating agents represent a valuable class of
therapeutics
for the treatment of cancer. An area of active research is expanding
the types of these therapeutics that are available to patients via
targeting new biological mechanisms. Hematopoietic progenitor kinase
1 (HPK1) is a negative regulator of immune signaling and a target
of high interest for the treatment of cancer. Herein, we present the
discovery and optimization of novel amino-6-aryl pyrrolopyrimidine
inhibitors of HPK1 starting from hits identified via virtual screening.
Key components of this discovery effort were structure-based drug
design aided by analyses of normalized B-factors
and optimization of lipophilic efficiency.