New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

  • Cell Chem Biol. 2023 Jun 15;30(6):618-631.e12. doi: 10.1016/j.chembiol.2023.05.007.
Matthew L Arwood  1 ,  Yao Liu  2 ,  Shannon K Harkins  3 ,  David M Weinstock  4 ,  Lei Yang  3 ,  Kristen E Stevenson  5 ,  Olivia D Plana  3 ,  Jingyun Dong  6 ,  Haley Cirka  3 ,  Kristen L Jones  3 ,  Anniina T Virtanen  7 ,  Dikshat G Gupta  1 ,  Amanda Ceas  1 ,  Brian Lawney  8 ,  Akinori Yoda  3 ,  Catharine Leahy  3 ,  Mingfeng Hao  2 ,  Zhixiang He  2 ,  Hwan Geun Choi  2 ,  Yaning Wang  9 ,  Olli Silvennoinen  7 ,  Stevan R Hubbard  6 ,  Tinghu Zhang  9 ,  Nathanael S Gray  10 ,  Loretta S Li  11
Affiliations
  • 1. Molecular and Translational Cancer Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Biology Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115, USA.
  • 5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 6. Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA; Skirball Institute of Biomolecular Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA.
  • 7. Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • 8. Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 9. Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 10. Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
  • 11. Molecular and Translational Cancer Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Division of Hematology, Oncology, and Stem Cell Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 37290440 DOI: 10.1016/j.chembiol.2023.05.007
Abstract

Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and Other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the "DFG-out" conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 Inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.

Keywords
B-ALL; CHZ868; CRLF2; JAK2; kinase; myeloproliferative neoplasm; resistance; ruxolitinib; type II inhibitor.
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