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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-12-09 DOI:10.1021/acs.jmedchem.4c01930

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 K. Ahmad, Louise Bernier, Simon Berritt, John Braganza, Zecheng Chen, Julie A. Cianfrogna, Michael Collins, Cinthia Costa Jones, Ciaran N. Cronin, Carl Davis, Klaus Dress, Martin Edwards, William Farrell, Scott P. France, Nicole Grable, Eric Johnson, Ted W. Johnson, Rhys Jones, Thomas Knauber, Jennifer Lafontaine, Richard P. Loach, Michael Maestre, Nichol Miller, Mark Moen, Sebastien Monfette, Peter Morse, Andrew Ross Nager, Mark Niosi, Paul Richardson, Allison K. Rohner, Neal W. Sach, Sergei Timofeevski, Joseph W. Tucker, Beth Vetelino, Lei Zhang, Sajiv K. Nair

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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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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.