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

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.

SUBMITTER: Alcock LJ 

PROVIDER: S-EPMC8919382 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature