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Development of Potent and Selective Janus Kinase 2/3 Directing PG-PROTACs.

Lisa J Alcock1, Yunchao Chang1, Jamie A Jarusiewicz2

  • 1Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.

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Researchers developed novel PROTACs targeting JAK2/3 kinases, crucial in blood cancers and autoimmune diseases. One compound, SJ10542, showed high selectivity and potency against specific leukemia cells.

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Area of Science:

  • Molecular Biology
  • Medicinal Chemistry
  • Oncology

Background:

  • Aberrant Janus kinase-Signal transducer and activator of transcription (JAK-STAT) pathway activation is linked to hematological malignancies and autoimmune disorders.
  • Targeting specific JAK family members offers a therapeutic strategy for these conditions.

Purpose of the Study:

  • To design, synthesize, and characterize novel Proteolysis-Targeting Chimeras (PROTACs) targeting JAK2 and JAK3 kinases.
  • To evaluate the selectivity and efficacy of these PROTACs in relevant cellular models.

Main Methods:

  • PROTACs were designed using a phenyl glutarimide (PG) ligand to recruit Cereblon (CRBN).
  • Synthesis and chemical characterization of the developed PROTACs were performed.
  • In vitro assays assessed selectivity against GSPT1 and other JAK family members, and cellular potency was tested in patient-derived Acute Lymphoblastic Leukemia (ALL) cells.

Main Results:

  • The PROTAC SJ10542 demonstrated high selectivity for JAK2/3 over GSPT1 and other JAK family kinases.
  • SJ10542 exhibited significant potency in patient-derived ALL cells harboring specific genetic alterations (JAK2 fusions and CRLF2 rearrangements).

Conclusions:

  • Novel JAK2/3 PROTACs were successfully designed and synthesized.
  • SJ10542 represents a promising selective inhibitor for hematological malignancies driven by JAK-STAT pathway dysregulation.