9CZX

HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 21

This is a non-PDB format compatible entry.

Summary for 9CZX

• Entry DOI: 10.2210/pdb9czx/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 1, 4-[(1R)-1-aminopropyl]-2-{6-[(4S,5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: kinase, 3d domain swap, inactive state, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70462.98

Authors

Johnson, E.,Mc Tigue, M. (deposition date: 2024-08-05, release date: 2024-12-18, Last modification date: 2025-01-08)

Primary citation

Gallego, R.A.,Cho-Schultz, S.,Del Bel, M.,Dechert-Schmitt, A.M.,Donaldson, J.S.,He, M.,Jalaie, M.,Kania, R.,Matthews, J.,McTigue, M.,Tuttle, J.B.,Risley, H.,Zhou, D.,Zhou, R.,Ahmad, O.K.,Bernier, L.,Berritt, S.,Braganza, J.,Chen, Z.,Cianfrogna, J.A.,Collins, M.,Costa Jones, C.,Cronin, C.N.,Davis, C.,Dress, K.,Edwards, M.,Farrell, W.,France, S.P.,Grable, N.,Johnson, E.,Johnson, T.W.,Jones, R.,Knauber, T.,Lafontaine, J.,Loach, R.P.,Maestre, M.,Miller, N.,Moen, M.,Monfette, S.,Morse, P.,Nager, A.R.,Niosi, M.,Richardson, P.,Rohner, A.K.,Sach, N.W.,Timofeevski, S.,Tucker, J.W.,Vetelino, B.,Zhang, L.,Nair, S.K.
Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.
J.Med.Chem., 67:22002-22038, 2024

PubMed 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 (, 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.

PubMed: 39651809
DOI: 10.1021/acs.jmedchem.4c01930

Experimental method

X-RAY DIFFRACTION (1.464 Å)