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Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

We evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Solving the structure of FDA-approved type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 JH1 tyrosine kinase domain enabled the rational design and optimization of Cereblon (CRBN)-directed JAK PROTACs utilizing multiple derivatives of JAK inhibitors, linkers and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation by proteomic approaches, and activity tested in CRLF2-rearranged cell line and xenograft models of ALL.

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Dataset ID Description Technology Samples
EGAD00001007569 Illumina NovaSeq 6000 11
EGAD00001007570 Illumina NovaSeq 6000 11
Publications Citations
Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.
Blood 138: 2021 2313-2326
22