PO.ET09.04 · 实验与分子治疗
发现具有卓越抗白血病疗效的强效CDK8/CDK19 PROTAC降解剂
Discovery of potent CDK8/CDK19 PROTAC degraders with superior anti-leukemia efficacy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
侵袭性白血病，包括急性髓系白血病（AML），由于缺乏治愈性疗法，仍然是极具挑战性的疾病。AML对常规和靶向治疗均能迅速产生耐药性，凸显了对更有效治疗策略的迫切需求。近来，调控转录的中介体激酶CDK8和CDK19已成为有前景的靶点，CDK8/19激酶抑制剂（CDK8/19i）目前正在开展白血病临床试验。然而，我们实验室的初步数据表明，白血病细胞系对CDK8/19i表现出异质性且往往不完全的应答，许多细胞在最初敏感后产生耐药。为验证以下假设——直接清除CDK8/19蛋白（相较于仅抑制激酶活性）可能引发更强效、更持久的抗白血病活性，我们基于选择性CDK8/19抑制剂，通过多种连接子与招募cereblon（CRBN）的配体偶联，开发了三个系列的蛋白降解靶向嵌合体（PROTAC）。在对激酶靶向弹头和连接子组成进行广泛优化后，所获得的最强效降解剂SNX7886在多种细胞类型中以10 nM的DC50诱导CDK8和CDK19的高效同步降解。当与其同源CDK8/19i（BI1347）并行评估时，SNX7886在多种白血病细胞系中始终产生更卓越且持续的生长抑制，而未出现CDK8/19激酶抑制剂所观察到的适应性耐药。值得注意的是，在侵袭性难治性AML细胞系NOMO1中，长期使用CDK8/19-PROTAC处理导致完全生长停滞，在延长暴露期间检测不到存活细胞。转录组学和蛋白质组学分析进一步揭示，与CDK8/19i相比，CDK8/19-PROTAC参与了共有和独特的分子通路，表明其对与AML存活和适应相关的转录重编程回路造成了更深层次的破坏。这些发现凸显了靶向CDK8/19降解作为一种有前景的治疗策略，能够克服CDK8/19激酶抑制剂在AML中的关键局限性。
查看英文原文 English abstract
Aggressive leukemias, including acute myeloid leukemia (AML), remain highly challenging diseases due to the lack of curative therapies. AML rapidly develops resistance to both conventional and targeted treatments, underscoring the urgent need for more effective therapeutic strategies. Recently, the transcription-regulating Mediator kinases CDK8 and CDK19 have emerged as promising targets, with CDK8/19 kinase inhibitors (CDK8/19i) now in clinical trials for leukemia. However, preliminary data from our laboratory demonstrate that leukemia cell lines exhibit heterogeneous and often incomplete responses to CDK8/19i, with many developing resistance after initial sensitivity. To test the hypothesis that direct depletion of CDK8/19 proteins in contrast to inhibiting kinase activity alone, may elicit more potent and durable anti-leukemia activity, we developed three series of PROteolysis TArgeting Chimeras (PROTACs) based on selective CDK8/19 inhibitors conjugated through diverse linkers to cereblon (CRBN)-recruiting ligands. After extensive optimization of both the kinase targeted warhead and composition of the linker, the most potent degrader obtained, SNX7886, induced efficient and simultaneous degradation of CDK8 and CDK19 across multiple cell types with a DC 50 of 10 nM. When evaluated side-by-side with its cognate CDK8/19i (BI1347), SNX7886 consistently produced superior and sustained growth inhibition without the adaptive resistance observed with CDK8/19 kinase inhibitors in multiple leukemia lines. Notably, in an aggressive refractory AML cell line NOMO1, prolonged treatment with CDK8/19-PROTACs resulted in complete growth arrest, with no surviving cells detectable over extended exposure. Transcriptomic and proteomic analyses further revealed that CDK8/19-PROTACs engage both shared and distinct molecular pathways compared to CDK8/19i, indicating deeper disruption of transcriptional reprogramming circuits associated with AML survival and adaptation. These findings highlight targeted CDK8/19 degradation as a promising therapeutic strategy capable of overcoming key limitations of CDK8/19 kinase inhibitors in AML.
利益披露 Disclosure
L. Zhang, None..
J. Zheng, None..
R. Martin, None..
J. Li, None..
Z. T. Mack, None..
H. Ji, None..
E. V. Broude, None..
I. B. Roninson, None..
C. McInnes, None..
M. Chen, None.