ArticleBlood2021
Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.
Article in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 3 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
45 citing papers in PubMed, 3 syntheses or guidelines pooled it, 65 citations in OpenAlex.
- Prognostic significance of CRLF2 in patients with acute lymphoblastic leukemia: a meta-analysis and systematic review.Annals of hematology · 2024Pooled it
- Circulating tumor cells in peripheral blood as a diagnostic biomarker of breast cancer: A meta-analysis.Frontiers in oncology · 2023Pooled it
- JAK inhibitors and COVID-19.Journal for immunotherapy of cancer · 2022Pooled it
- Nucleo-amino acid derived AMO as a potential JAK inhibitor: machine learning screening, docking, molecular dynamics, ADMET/toxicity, and MM-PBSA analysis.Current research in structural biology · 2026Article
- Unraveling the secrets of novel PROTACs to improve degradation efficacy.Molecular diversity · 2026Review
- Review
- Safety considerations for cereblon-recruiting targeted protein degraders.Nature reviews. Drug discovery · 2026Review
- Endophytic Aspergillus glaucus as a novel epothilone B producer: Antiproliferative activity and in silico analysis.Applied microbiology and biotechnology · 2026Article
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- Targeting BCL-xL in Myeloid Malignancies: From Inhibitors to PROTAC.Journal of cellular and molecular medicine · 2026Review
- Prospects and advances of PROTAC in the treatment of hematologic malignancies.Experimental hematology & oncology · 2026Review
- STAT-independent functions of Janus kinases 1 and 2 are obligatory for the postnatal development of mammary epithelial ducts.Cell reports · 2026Article
- Revisiting Janus kinases as molecular drug targets for rheumatic diseases.Frontiers in medicine · 2026Review
- Assessment of flonoltinib maleate versus ruxolitinib phosphate in intermediate- to high-risk myelofibrosis (FMF-02): study protocol for a multicenter, randomized, open-label phase IIB trial.Therapeutic advances in hematology · 2026Article
- Cancer Biology of GSPT1: Mechanisms and Targeted Therapy Opportunities of Molecular Glue Degraders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Expanding the Scope of PROTACs: Opportunities and Challenges in Topical Delivery.Journal of medicinal chemistry · 2025Review
- CSF2RA promotes gastric cancer progression through activation of the JAK2/STAT3 signaling pathway.Journal of molecular histology · 2025Article
- An Interpretable Deep Learning and Molecular Docking Framework for Repurposing Existing Drugs as Inhibitors of SARS-CoV-2 Main Protease.Molecules (Basel, Switzerland) · 2025Article
- Recent advances and future perspectives in small molecule JAK2 inhibitors.Future medicinal chemistry · 2025Review
- Impact of Ruxolitinib Interactions on JAK2 JH1 Domain Dynamics.International journal of molecular sciences · 2025Article
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Authors and funding
27 authors at 7 institutions in 3 countries.
Funding
Abstract
CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT-driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.