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

  • ACS Med Chem Lett. 2022 Feb 21;13(3):475-482. doi: 10.1021/acsmedchemlett.1c00650.
Lisa J Alcock  1 ,  Yunchao Chang  1 ,  Jamie A Jarusiewicz  2 ,  Marisa Actis  2 ,  Stanley Nithianantham  2 ,  Anand Mayasundari  2 ,  Jaeki Min  2 ,  Dylan Maxwell  3 ,  Jeremy Hunt  3 ,  Brandon Smart  3 ,  Jun J Yang  3 ,  Gisele Nishiguchi  2 ,  Marcus Fischer  2  4 ,  Charles G Mullighan  1  5 ,  Zoran Rankovic  2
Affiliations
  • 1. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 3. Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5. Hematological Malignancies Program, St. Jude Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
PMID: 35300081 DOI: 10.1021/acsmedchemlett.1c00650
Abstract

Aberrant activation of the JAK-STAT signaling pathway has been implicated in the pathogenesis of a range of hematological malignancies and autoimmune disorders. Here we describe the design, synthesis, and characterization of JAK2/3 PROTACs utilizing a phenyl glutarimide (PG) ligand as the Cereblon (CRBN) recruiter. SJ10542 displayed high selectivity over GSPT1 and Other members of the JAK family and potency in patient-derived ALL cells containing both JAK2 fusions and CRLF2 rearrangements.

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