美国哈佛大学化学与化学生物学系Christina M. Woo和美国纪念斯隆凯特琳癌症中心Michael G. Kharas团队合作发现，IKZF2和酪蛋白激酶1α（CK1α）双降解剂靶向急性髓系白血病（AML）细胞。相关论文于2023年3月9日发表在《癌细胞》杂志上。

他们报告了IKZF2和CK1α的大脑依赖性降解剂的研发，称为DEG-35和DEG-77。他们利用结构引导的方法开发DEG-35作为IKZF2的纳摩尔降解剂，IKZF2是一种有助于骨髓白血生成的造血特异性转录因子。DEG-35对治疗相关靶标CK1α具有额外的底物特异性，该靶标通过无偏倚蛋白质组学和PRISM筛选实验鉴定。IKZF2和CK1α的降解阻断细胞生长，并通过CK1α-p53-和IKZF2依赖性途径诱导AML细胞中的骨髓分化。通过DEG-35或更易溶的类似物DEG-77降解靶标，延缓小鼠和人AML小鼠模型中的白血病进展。

总体而言，他们提供了一种IKZF2和CK1α的多靶点降解策略，以提高对AML的疗效，并可能扩展到其他靶点和适应症。

研究人员表示，AML是一种血液系统恶性肿瘤，已被确定几种表观遗传调节因子作为治疗靶点。

附：英文原文

Title: Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

Author: Sun-Mi Park, David K. Miyamoto, Grace Y.Q. Han, Mandy Chan, Nicole M. Curnutt, Nathan L. Tran, Anthony Velleca, Jun Hyun Kim, Alexandra Schurer, Kathryn Chang, Wenqing Xu, Michael G. Kharas, Christina M. Woo

Issue&Volume: 2023-03-09

Abstract: Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigeneticregulators have been identified as therapeutic targets. Here we report the developmentof cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolardegrader of IKZF2, a hematopoietic-specific transcription factor that contributesto myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for thetherapeutically relevant target CK1α, which was identified through unbiased proteomicsand a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and inducesmyeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways.Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progressionin murine and human AML mouse models. Overall, we provide a strategy for multitargeteddegradation of IKZF2 and CK1α to enhance efficacy against AML that may be expandedto additional targets and indications.

DOI: 10.1016/j.ccell.2023.02.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00038-7