TY - JOUR
T1 - Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia
AU - Chang, Yunchao
AU - Min, Jaeki
AU - Jarusiewicz, Jamie A.
AU - Actis, Marisa
AU - Yu-Chen Bradford, Shanshan
AU - Mayasundari, Anand
AU - Yang, Lei
AU - Chepyala, Divyabharathi
AU - Alcock, Lisa J.
AU - Roberts, Kathryn G.
AU - Nithianantham, Stanley
AU - Maxwell, Dylan
AU - Rowland, Lauren
AU - Larsen, Randolph
AU - Seth, Aman
AU - Goto, Hiroaki
AU - Imamura, Toshihiko
AU - Akahane, Koshi
AU - Hansen, Baranda S.
AU - Pruett-Miller, Shondra M.
AU - Paietta, Elisabeth M.
AU - Litzow, Mark R.
AU - Qu, Chunxu
AU - Yang, Jun J.
AU - Fischer, Marcus
AU - Rankovic, Zoran
AU - Mullighan, Charles G.
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/12/9
Y1 - 2021/12/9
N2 - 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.
AB - 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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U2 - 10.1182/blood.2020006846
DO - 10.1182/blood.2020006846
M3 - Article
C2 - 34110416
AN - SCOPUS:85118966784
SN - 0006-4971
VL - 138
SP - 2313
EP - 2326
JO - Blood
JF - Blood
IS - 23
ER -