St. Jude Reference #SJ-19-0047
Researchers at St. Jude have developed small molecule conjugates of JAK1/JAK2 inhibitor binders, which can be used for development of the treatment of CRLF2r and JAK-STAT driven ALL. CRLF2-rearranged ALL comprises up to 60% of Philadelphia-like (Ph-like, BCR ABL1-like) acute lymphoblastic leukemia (ALL), and up to 15% of B-ALL overall, and is associated with high risk features and poor outcome. Targeting of this pathway with type I JAK inhibitors such as ruxolitinib results in variable inhibition of signaling and proliferation in vivo, and emerging clinical data indicate suboptimal responses to ruxolitinib. Thus, new approaches to abrogate JAK-STAT signaling are urgently required to improve the dismal outcomes for CRLF2r ALL patients and may have broader therapeutic application in other JAK-STAT driven malignancies.
The researchers have advanced their studies to include several PROTACs based on multiple compounds and modified analogs (Ruxolitinib, Creblon, Baricitinib; and other conjugates), with 1,000x higher efficacy and improved results.
Small molecule, JAK1/JAK2 inhibitor binders, CRLF2r and JAK-STAT driven ALL, Ruxolitinib, Creblon, Baricitinib.
Granted patents or published applications
A pending patent application published as WO 2021/022076
Related scientific references
Chang, et al., “Degradation of Janus kinases in CRLF2 -rearranged acute lymphoblastic leukemia,” Blood (2021) 138 (23): 2313–2326.
Gocho, Y., Liu, J., Hu, J. et al. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia. Nat Cancer 2, 284–299 (2021). https://doi.org/10.1038/s43018-020-00167-4
Lisa J. Alcock, Yunchao Chang, Jamie A. Jarusiewicz, Marisa Actis, Stanley Nithianantham, Anand Mayasundari, Jaeki Min, Dylan Maxwell, Jeremy Hunt, Brandon Smart, Jun J. Yang, Gisele Nishiguchi, Marcus Fischer, Charles G. Mullighan, and Zoran Rankovic, “Development of Potent and Selective Janus Kinase 2/3 Directing PG–PROTACs,” ACS Medicinal Chemistry Letters 2022 13 (3), 475-482, DOI: 10.1021/acsmedchemlett.1c00650
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