Development of Potent and Selective Janus Kinase 2/3 Directing PG–PROTACs
Lisa J. Alcock, Yunchao Chang, Jamie Jarusiewicz, Marisa Actis, Stanley Nithianantham, Anand Mayasundari, Jaeki Min, Dylan Maxwell, Jeremy P. Hunt, Brandon Smart, Jun J. Yang, Gisele Nishiguchi, Marcus Fischer, Charles G. Mullighan, Zoran Ranković
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.
Topics & Concepts
Janus kinaseCereblonKinaseChemistryJAK-STAT signaling pathwayCancer researchSignal transductionMedicinePharmacologyTyrosine kinaseBiochemistryGeneUbiquitin ligaseUbiquitinProtein Degradation and InhibitorsCAR-T cell therapy researchLymphoma Diagnosis and Treatment