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Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

ABSTRACT: 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.

PROVIDER: EGAS00001005180 | EGA |

REPOSITORIES: EGA

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Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

Project description:The type I JAK inhibitor ruxolitinib is approved for therapy of MPN patients but evokes resistance with longer exposure. Several novel type I JAK inhibitors were studied and we show that they uniformly induce resistance via a shared mechanism of JAK family heterodimer formation.Here we studied the expression profiles of SET2 cell lines persistent to several different type I JAK inhibitors in comparison to naive SET2 cells or in comparison to SET2 cells with acute exposure to ruxolitinib. Analysis of RNA isolated from several type I JAK inhibitor SET2 cell lines in comparison to naïve SET2 cells

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Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment

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2018-10-24 | PXD006581 | Pride

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (RNA-seq)

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JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (ChIP-seq)

2021-04-23 | GSE161663 | GEO

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2021-04-23 | GSE161665 | GEO

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