Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia
Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia
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DOI：
10.1182/blood.2020006846
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发表时间：
2021-12-09
期刊：
影响因子：
20.3
通讯作者：
Mullighan, Charles G.
中科院分区：
文献类型：
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作者：
Chang, Yunchao;Min, Jaeki;Mullighan, Charles G.
CRLF2 重排 (CRLF2r) 急性淋巴细胞白血病 (ALL) 占费城染色体样 (Ph-like) ALL 的一半以上，并且与儿童和成人的不良预后相关。 CRLF2 的过度表达会导致实验模型中 Janus 激酶 (JAK)-STAT 和平行信号通路的激活，但现有的 JAK 小分子抑制剂显示出可变且有限的功效。在这里，我们评估了针对 JAK 的蛋白水解靶向嵌合体 (PROTAC) 的功效。解决与 JAK2 酪氨酸激酶结构域结合的 I 型 JAK 抑制剂 ruxolitinib 和 baricitinib 的结构，能够合理设计和优化一系列利用 JAK 抑制剂衍生物、接头和 CRBN 特异性分子胶的 cereblon (CRBN) 导向的 JAK PROTAC。对所得 JAK PROTAC 的目标降解进行了评估，并在一组白血病/淋巴瘤细胞系和激酶驱动的 ALL 异种移植模型中测试了活性。开发了多种 PROTAC 来降解 JAK 并有效杀死 CRLF2r 细胞系，其中最活跃的 PROTAC 还降解已知的 CRBN 新底物 GSPT1 并抑制体内 CRLF2r ALL 的增殖，例如化合物 7 (SJ988497)。虽然双重 JAK/GSPT1 降解 PROTAC 是最有效的，但在扩展的异种移植物组中对多个 PROTAC 的开发和评估发现了一种有效的 JAK2 降解、保留 GSPT1 的 PROTAC，该 PROTAC 在大多数激酶驱动的异种移植物中表现出功效，这些异种移植物对 I 型 JAK 抑制剂没有反应，例如 I 型 JAK 抑制剂。化合物8(SJ1008030)。总之，这些数据显示了 JAK 引导的蛋白质降解作为 JAK-STAT 驱动的 ALL 治疗方法的潜力，并强调了 JAK 和 GSPT1 降解活性在这种情况下的相互作用。
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.