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

Lisa J AlcockYunchao ChangJamie A JarusiewiczMarisa ActisStanley NithiananthamAnand MayasundariJaeki MinDylan MaxwellJeremy HuntBrandon SmartJun J YangGisele NishiguchiMarcus FischerCharles G MullighanZoran Rankovic

Published in: ACS medicinal chemistry letters (2022)

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.

Keyphrases

induced apoptosis
signaling pathway
cell cycle arrest
pi k akt
multiple sclerosis
epithelial mesenchymal transition
cell death
disease activity
protein kinase
rheumatoid arthritis
cell proliferation