한빛사논문
- 조회878
1Yunchao Chang*, 2Jaeki Min*, 2Jamie A. Jarusiewicz, 2Marisa Actis, 2Shanshan Yu, 2Anand Mayasundari, 2Lei Yang, 2Divyabharathi Chepyala, 1Lisa Alcock, 1Kathryn G. Roberts, 2Stanley Nithianantham, 3Dylan Maxwell, 3Lauren Rowland, 3,11Randolph Larsen, 1Aman Seth, 4Hiroaki Goto, 5Toshihiko Imamura, 6Koshi Akahane, 7Baranda S. Hansen, , 7Shondra M. Pruett-Miller, 8Elisabeth Paietta, , 9Mark R. Litzow, 1Chunxu Qu, 3Jun J. Yang, 2,10,12Marcus Fischer**, 2,12Zoran Rankovic**, 1,13Charles G. Mullighan**
1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
2Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
4Division of Hemato-Oncology/Regenerative Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan
5Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
6Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
7Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis,TN
8Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
9Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
10Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN
11Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
12Cancer Biology Program, St. Jude Children’s Research Hospital, Memphis, TN
13Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, TN
*Y.C. and J.M. contributed equally
**co-corresponding authors
Abstract
CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) comprises over half of Philadelphia chromosome-like (Ph-like) ALL, is associated with poor outcome in children and adults. Overexpression of CRLF2 results in activation of JAK-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of Janus kinases show variable and limited efficacy. Here we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. 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 multiple 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 tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded Janus kinases and potently killed CRLF2-rearranged cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1, and suppressed proliferation of CRLF2-rearranged ALL in vivo. While dual JAK/GSPT1-degrading PROTACs were most potent, 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 the kinase-driven xenografts which were otherwise unresponsive to type I JAK inhibitors. 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 Janus kinase and GSPT1 degradation activity in this context.
논문정보
- Research article
- 2021년 06월 (BRIC 등록일 2021-06-21)
- 국외 연구진
- 의약학 > 약학
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