PO.CL12.03 · 临床研究
天然结构域相互作用重连使前列腺癌中的AR新增强体复合物崩溃
Native domain-interaction rewiring collapses the AR neo-enhanceosome in prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
雄激素受体（AR）信号轴在转移性去势抵抗性前列腺癌（mCRPC）中通过适应性机制保持活跃，尽管进行了雄激素剥夺，仍维持致癌转录程序。AR与组蛋白乙酰转移酶p300及其他辅因子协同，通过高度有序的结构域-结构域相互作用组装癌症特异性的"新增强体复合物（neo-enhanceosomes）"，从而驱动致癌基因表达。在此，我们引入一类新型化学诱导邻近化合物，称为结构域改变嵌合体（Domain-ALTeration Chimeras，DALTACs），它代表一种独特的模式，旨在通过改变天然结构域相互作用来重连内源性蛋白复合物，而非降解或抑制单个蛋白。我们的首创化合物AR-p300 DALTAC-1，强制AR配体结合结构域与p300溴结构域之间发生邻近，从而错误连接其天然架构并将复合物锁定在非产生性构型。这种结构域重构引发一种"超抑制"效应，比同时抑制AR和p300更强效地抑制AR靶基因转录和细胞增殖。从机制上讲，DALTAC-1重编程了p300的底物谱，减少组蛋白H2B N末端乙酰化（H2BNTac）并触发致癌增强子网络的崩溃。引人注目的是，DALTAC-1表现出显著的谱系选择性，在AR驱动的前列腺癌细胞和类器官中发挥强效活性，同时保留AR阴性或非前列腺谱系组织。在多种前列腺癌模型中，DALTAC-1表现出强健的抗肿瘤疗效和肿瘤消退，且耐受性良好。总之，本研究确立了DALTAC模式作为一种新的治疗概念，它操纵蛋白复合物拓扑结构以重编程细胞功能，为跨不同癌症类型重连多样化的转录、表观遗传和信号复合物提供了一种通用且可推广的策略。重要的是，DALTAC-1精确的谱系选择性将对正常组织的影响降至最低，凸显了其强大的临床转化潜力和较低的安全性顾虑可能性。
查看英文原文 English abstract
The androgen receptor (AR) signaling axis remains active in metastatic castration-resistant prostate cancer (mCRPC) through adaptive mechanisms that sustain oncogenic transcriptional programs despite androgen deprivation. AR cooperates with the histone acetyltransferase p300 and other cofactors to assemble cancer-specific “neo-enhanceosomes” via highly organized domain-domain interactions that drive oncogenic gene expression. Here, we introduce a new class of chemical-induced proximity compounds, termed Domain-ALTeration Chimeras (DALTACs), which represent a distinct modality designed to rewire endogenous protein complexes by altering native domain interactions rather than degrading or inhibiting individual proteins. Our first-in-class compound, AR-p300 DALTAC-1, enforces proximity between the AR ligand-binding domain and the p300 bromodomain, thereby miswiring their native architecture and locking the complex in a non-productive configuration. This domain reconfiguration elicits a “super-inhibitory” effect that suppresses AR target gene transcription and cell proliferation more potently than concurrent inhibition of AR and p300. Mechanistically, DALTAC-1 reprograms the substrate spectrum of p300, diminishing histone H2B N-terminal acetylation (H2BNTac) and triggering the collapse of the oncogenic enhancer network. Strikingly, DALTAC-1 displays remarkable lineage selectivity, exerting potent activity in AR-driven prostate cancer cells and organoids while sparing AR-negative or non-prostate lineage tissues. In multiple prostate cancer models, DALTAC-1 exhibits robust antitumor efficacy and tumor regression with favorable tolerability. Collectively, this study establishes the DALTAC modality as a new therapeutic concept that manipulates protein complex topology to reprogram cellular function, offering a versatile and generalizable strategy to rewire diverse transcriptional, epigenetic, and signaling complexes across different cancer types. Importantly, the exquisite lineage selectivity of DALTAC-1 minimizes effects on normal tissues, underscoring its strong clinical translational potential with a low likelihood of safety concerns.
利益披露 Disclosure
J. Luo, None..
S. Das, None..
J. Cai, None.