非降解子依赖的KAT2A招募：CRBN分子胶水靶标谱的新拓展，这一成果由美国Dana-Farber癌症研究所Eric S. Fischer研究组经过不懈努力而取得。该研究于2026年7月9日发表于国际一流学术期刊《科学》杂志上。

通过将基于小脑（CRBN）的分子胶扩展到规范的降解空间之外，小组开发了一种精细选择性的KAT2A降解剂。低温电子显微镜显示，CRBN独立于一个降解子招募KAT2A；相反，分子胶与表面暴露的酪氨酸结合，模拟类似抗体的分子识别。选择性KAT2A降解导致组蛋白H3赖氨酸9乙酰化（H3K9Ac）的有效消融，在急性髓系白血病细胞系中具有抗增殖作用，并在患者来源的异种移植模型中具有体内疗效，建立了KAT2A作为治疗多种恶性肿瘤的可靶向易损。更普遍的是，退化非依赖性招募扩展了CRBN靶向蛋白质组。

据介绍，赖氨酸乙酰转移酶（KATs）与癌基因如c-Myc、雌激素受体和赖氨酸甲基转移酶2A （KMT2A）合作，以阻止恶性程序。靶向KAT蛋白已显示出临床疗效；然而，实现大多数KATs的同源选择性仍然是一个主要挑战。

附：英文原文

Title: Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues

Author: Samuel Ojeda, Meng Wang, Kheewoong Baek, Wallace Bourgeois, Alba Sommerschield, Hong Yue, Rebecca J. Metivier, Panos Karagiannis, Talya S. Levitz, Yuan Xiong, Katherine A. Donovan, Scott A. Armstrong, Eric S. Fischer

Issue&Volume: 2026-07-09

Abstract: Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)–based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo–electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.

DOI: aef5391

Source: https://www.science.org/doi/10.1126/science.aef5391

期刊信息

Science：《科学》，创刊于1880年。隶属于美国科学促进会，最新IF：63.714

官方网址：https://www.sciencemag.org/

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