Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer
Rebecca A. Gallego, Sujin Cho-Schultz, Matthew Del Bel, Anne‐Marie Dechert‐Schmitt, Joyann S. Donaldson, Mingying He, Mehran Jalaie, Rob Kania, Jean Matthews, Michele McTigue, Jamison B. Tuttle, Hud Risley, Dahui Zhou, Ru Zhou, Omar Ahmad, Louise Bernier, Simon Berritt, John Braganza, Zecheng Chen, Julie Cianfrogna, Michael R. Collins, Cinthia Costa Jones, Ciarán N. Cronin, Carl Davis, Klaus Dress, Martin P. Edwards, William Farrell, Scott P. France, Nicole Grable, Eric F. Johnson, Ted W. Johnson, Rhys Jones, Thomas Knauber, Jennifer Lafontaine, Richard P. Loach, Michael Maestre, Nichol Miller, Mark A. Moen, Sébastien Monfette, Peter Morse, Andrew R. Nager, Mark Niosi, Paul Richardson, Allison Rohner, Neal W. Sach, Sergei Timofeevski, Joseph W. Tucker, Beth C. Vetelino, Lei Zhang, Sajiv K. Nair
Abstract
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.