2. Academic Validation
  3. ZNL0325, a Pyrazolopyrimidine-Based Covalent Probe, Demonstrates an Alternative Binding Mode for Kinases

ZNL0325, a Pyrazolopyrimidine-Based Covalent Probe, Demonstrates an Alternative Binding Mode for Kinases

  • J Med Chem. 2024 Feb 1. doi: 10.1021/acs.jmedchem.3c01891.
Zhengnian Li 1,  Wenchao Lu 2,  Tyler S Beyett 3 4,  Scott B Ficarro 3 5 6,  Jie Jiang 7 8,  Jason Tse 1,  Audrey Yong-Ju Kim 1,  Jarrod A Marto 3 5 6,  Jianwei Che 3 4,  Pasi A Jänne 7 8,  Michael J Eck 3 4,  Tinghu Zhang 1,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 2 Lingang Laboratory, Shanghai 200031, China.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 5 Blais Proteomics Center, Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 6 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 7 Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 8 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
PMID: 38300264 DOI: 10.1021/acs.jmedchem.3c01891
Abstract

The pyrazolopyrimidine (PP) heterocycle is a versatile and widely deployed core scaffold for the development of kinase inhibitors. Typically, a 4-amino-substituted pyrazolopyrimidine binds in the ATP-binding pocket in a conformation analogous to the 6-aminopurine of ATP. Here, we report the discovery of ZNL0325 which exhibits a flipped binding mode where the C3 position is oriented toward the ribose binding pocket. ZNL0325 and its analogues feature an acrylamide side chain at the C3 position which is capable of forming a covalent bond with multiple kinases that possess a cysteine at the αD-1 position including Btk, EGFR, Blk, and JAK3. These findings suggest that the ability to form a covalent bond can override the preferred noncovalent binding conformation of the heterocyclic core and provides an opportunity to create structurally distinct covalent kinase inhibitors.

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