Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

  • Blood. 2021 Dec 9;138(23):2313-2326. doi: 10.1182/blood.2020006846.
Yunchao Chang  1 ,  Jaeki Min  2 ,  Jamie A Jarusiewicz  2 ,  Marisa Actis  2 ,  Shanshan Yu-Chen Bradford  2 ,  Anand Mayasundari  2 ,  Lei Yang  2 ,  Divyabharathi Chepyala  2 ,  Lisa J Alcock  1 ,  Kathryn G Roberts  1 ,  Stanley Nithianantham  2 ,  Dylan Maxwell  3 ,  Lauren Rowland  3 ,  Randolph Larsen  3  4 ,  Aman Seth  1 ,  Hiroaki Goto  5 ,  Toshihiko Imamura  6 ,  Koshi Akahane  7 ,  Baranda S Hansen  8 ,  Shondra M Pruett-Miller  8 ,  Elisabeth M Paietta  9 ,  Mark R Litzow  10 ,  Chunxu Qu  1 ,  Jun J Yang  3  11 ,  Marcus Fischer  2  12  13 ,  Zoran Rankovic  2  13 ,  Charles G Mullighan  1  11
Affiliations
  • 1. Department of Pathology.
  • 2. Department of Chemical Biology and Therapeutics.
  • 3. Department of Pharmaceutical Sciences, and.
  • 4. Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN.
  • 5. Division of Hemato-Oncology/Regenerative Medicine, Kanagawa Children's Medical Center, Yokohama, Japan.
  • 6. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • 7. Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.
  • 8. Center for Advanced Genome Engineering, St Jude Children's Research Hospital, Memphis, TN.
  • 9. Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
  • 10. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN; and.
  • 11. Hematological Malignancies Program, St Jude Children's Research Hospital, Memphis, TN.
  • 12. Department of Structural Biology.
  • 13. Cancer Biology Program, and.
PMID: 34110416 DOI: 10.1182/blood.2020006846
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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