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

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

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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