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

• Published in: Journal of medicinal chemistry Vol. 67; no. 24; pp. 22002 - 22038
• Main Authors: Gallego, Rebecca A., Cho-Schultz, Sujin, Del Bel, Matthew, Dechert-Schmitt, Anne-Marie, Donaldson, Joyann S., He, Mingying, Jalaie, Mehran, Kania, Rob, Matthews, Jean, McTigue, Michele, Tuttle, Jamison B., Risley, Hud, Zhou, Dahui, Zhou, Ru, Ahmad, Omar K., Bernier, Louise, Berritt, Simon, Braganza, John, Chen, Zecheng, Cianfrogna, Julie A., Collins, Michael, Costa Jones, Cinthia, Cronin, Ciaran N., Davis, Carl, Dress, Klaus, Edwards, Martin, Farrell, William, France, Scott P., Grable, Nicole, Johnson, Eric, Johnson, Ted W., Jones, Rhys, Knauber, Thomas, Lafontaine, Jennifer, Loach, Richard P., Maestre, Michael, Miller, Nichol, Moen, Mark, Monfette, Sebastien, Morse, Peter, Nager, Andrew Ross, Niosi, Mark, Richardson, Paul, Rohner, Allison K., Sach, Neal W., Timofeevski, Sergei, Tucker, Joseph W., Vetelino, Beth, Zhang, Lei, Nair, Sajiv K.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.12.2024; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Chemistry, Medicinal; Drug Discovery; Humans; Life Sciences & Biomedicine; Molecular Structure; Neoplasms - drug therapy; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Science & Technology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; SECONDARY; IMMUNITY; DESIGN; CYP2D6
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01930

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.