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

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

  • J Med Chem. 2024 Dec 26;67(24):22002-22038. doi: 10.1021/acs.jmedchem.4c01930.
Rebecca A Gallego 1 Sujin Cho-Schultz 1 Matthew Del Bel 1 Anne-Marie Dechert-Schmitt 2 Joyann S Donaldson 1 Mingying He 1 Mehran Jalaie 1 Rob Kania 1 Jean Matthews 1 Michele McTigue 1 Jamison B Tuttle 3 Hud Risley 2 Dahui Zhou 2 Ru Zhou 1 Omar K Ahmad 3 Louise Bernier 1 Simon Berritt 2 John Braganza 1 Zecheng Chen 2 Julie A Cianfrogna 4 Michael Collins 1 Cinthia Costa Jones 5 Ciaran N Cronin 1 Carl Davis 4 Klaus Dress 1 Martin Edwards 1 William Farrell 1 Scott P France 2 Nicole Grable 1 Eric Johnson 1 Ted W Johnson 1 Rhys Jones 4 Thomas Knauber 2 Jennifer Lafontaine 1 Richard P Loach 2 Michael Maestre 5 Nichol Miller 5 Mark Moen 2 Sebastien Monfette 2 Peter Morse 4 Andrew Ross Nager 5 Mark Niosi 2 Paul Richardson 1 Allison K Rohner 1 Neal W Sach 1 Sergei Timofeevski 5 Joseph W Tucker 2 Beth Vetelino 2 Lei Zhang 3 Sajiv K Nair 1
Affiliations

Affiliations

  • 1 Oncology Medicinal Chemistry Worldwide Research and Development, Pfizer, Inc., 10770 Science Center Drive, La Jolla, California 92121, United States.
  • 2 Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
  • 3 Worldwide Research and Development, Pfizer, Inc., Cambridge, Massachusetts 02139, United States.
  • 4 Pharmacokinetics, Dynamics and Metabolism Worldwide Research and Development, Pfizer, Inc., 10770 Science Center Drive, La Jolla, California 92121, United States.
  • 5 Oncology Research Unit Worldwide Research and Development, Pfizer, Inc., 10770 Science Center Drive, La Jolla, California 92121, United States.
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170443
    HPK1/MAP4K1 Inhibitor