PO.CH03.01 · 化学
首创的CHD4稳定型抑制剂，可捕获并解离NuRD复合物
First-in-class stabilizing inhibitor of CHD4 that traps and disassembles the NuRD complex
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摘要 Abstract
中文摘要
CHD4是NuRD复合物的催化核心，调控染色质重塑、转录抑制和DNA修复。其在胶质母细胞瘤中的过表达与不良预后相关，但CHD4一直难以成药。采用一种新型细胞靶点结合策略，我们鉴定出CH41——一种首创的小分子，可与CHD4染色质结构域中的胱氨酸残基共价结合。该化合物将CHD4稳定在染色质上，阻断其重塑活性，并诱导NuRD复合物解离和蛋白酶体降解。在发现和验证阶段均应用的MICRO-TAG®细胞靶点结合分析系统，证实了对CHD4的直接结合以及与机制性捕获相一致的实时胞内稳定化。CH41破坏CHD4与ZMYND8以及RBBP4/7的相互作用，抑制RAD51表达，并损害同源重组修复，导致RAD51焦点减少以及gammaH2AX和53BP1蓄积增加。在功能上，CH41使CHD4依赖性的DNA修复和转录调控失效，使替莫唑胺耐药的胶质母细胞瘤细胞重新敏感。这些数据确立了CH41作为首个选择性CHD4抑制剂的地位，并展示了细胞生物物理学和细胞靶点结合分析的进步如何正在改变对具有挑战性的转录因子靶点（如染色质重塑因子）小分子调节剂的发现。
查看英文原文 English abstract
CHD4, the catalytic core of the NuRD complex, regulates chromatin remodeling, transcriptional repression, and DNA repair. Its overexpression in glioblastoma correlates with poor prognosis, yet CHD4 has remained undruggable. Employing a novel cell target engagement strategy, we identified CH41, a first-in-class small molecule that covalently engages cystine residues in the CHD4 chromodomain. The compound stabilizes CHD4 on chromatin, blocks its remodeling activity, and induces NuRD complex dissociation and proteasomal degradation. MICRO-TAG® cellular target engagement assay system applied in both discovery and validation stages, confirms direct CHD4 binding and real-time intracellular stabilization consistent with mechanistic trapping. CH41 disrupts CHD4 interaction with ZMYND8 and RBBP4/7, represses RAD51 expression, and impairs homologous-recombination repair, leading to reduced RAD51 foci and increased gammaH2AX and 53BP1 accumulation. Functionally, CH41 disables CHD4-dependent DNA repair and transcriptional control, re-sensitizing temozolomide-resistant glioblastoma cells. The data establishes CH41 as the first selective CHD4 inhibitor and illustrates how advances in cellular biophysics and cellular target engagement profiling are transforming the discovery of small molecule modulators of challenging transcription factor targets, such as chromatin remodelers.
利益披露 Disclosure
A. Sanchez, None..
M. Kim, None..
K. Miller, None..
E. Nurmemmedov, None.