Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents
a high
interest target for the treatment of cancer through an immune-mediated
mechanism. Herein we present highlights of the drug discovery campaign
within the lactam/azalactam series of inhibitors that yielded a small
molecule (21, PF-07265028), which was advanced to a phase
1 clinical trial (NCT05233436). Key components of the discovery effort
included optimization of potency through mitigation of ligand strain
as guided by the use of cocrystal structures, mitigation of ADME liabilities
(plasma instability and fraction metabolism by CYP2D6), and optimization
of kinase selectivity, particularly over immune-modulating kinases
with high homology to HPK1. Structure-based drug design via leveraging
cocrystal structures and lipophilic efficiency analysis proved to
be valuable tools that ultimately enabled the delivery of a clinical-quality
small molecule inhibitor of HPK1.