PO.ET09.06 · 实验与分子治疗
结构导向设计的JZY3032——一种在前列腺癌中使AR-p300错误连接的双重结合DALTAC
Structure-guided design of JZY3032, a dual-engaging DALTAC that miswires AR-p300 in prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
化学诱导邻近（CIP）策略通过调控蛋白-蛋白相互作用拓展了治疗格局，然而当前大多数模式（如PROTAC和分子胶）将非生理性伙伴并置，往往产生可变或不可预测的结果。为解决这一局限，我们开发了结构域改造嵌合体（DALTAC），这是一种机制上截然不同的平台，通过在生理性伙伴之间强制形成非生产性的结构域-结构域相互作用，选择性地使内源性蛋白复合物错误连接。DALTAC并非降解靶标或稳定天然界面，而是通过理性配体选择和连接子工程重新配置多结构域复合物的拓扑结构。作为概念验证，我们设计了JZY3032——首创的AR-p300 DALTAC，用以使雄激素受体（AR）-p300转录复合物失活，该复合物是前列腺癌中的关键调控节点。在迭代药物化学优化的指导下，我们使用经调节的连接子将AR LBD抑制剂与选择性p300溴结构域抑制剂偶联，该连接子经优化以实现协同性、同时性的双重结合。所得构建体将生理性AR-p300相互作用界面重新导向为空间上错位、非生产性的构型，从而阻止AR N端结构域与p300的通讯并抑制增强子激活。机制特异性通过两种阴性对照类似物得到确认，这两种类似物分别选择性破坏AR或p300结合；二者均无生物学活性，表明DALTAC功能需要双重结合和结构域重构。SAR研究揭示，连接子长度、刚性及出口向量取向是复合物错误连接效率的关键决定因素。在功能上，JZY3032强效抑制AR和p300共依赖前列腺癌模型的生长，同时不影响AR阴性谱系，确立了工程化结构域错误连接所产生的谱系选择性治疗潜力。总体而言，这些数据确立了DALTAC作为一类新型基于邻近效应的疗法，能够通过拓扑工程使致癌转录复合物失活。JZY3032展示了一个广泛可扩展的模块化化学平台，可用于理性设计未来靶向多种疾病相关蛋白组装体的DALTAC分子。
查看英文原文 English abstract
Chemical-induced proximity (CIP) strategies have expanded the therapeutic landscape by modulating protein-protein interactions, yet most current modalities, such as PROTACs and molecular glues-juxtapose non-physiological partners, often yielding variable or unpredictable outcomes. To address this limitation, we developed Domain-ALTeration Chimeras (DALTACs), a mechanistically distinct platform that selectively miswires endogenous protein complexes by enforcing non-productive domain-domain interactions between physiologic partners. Rather than degrading targets or stabilizing native interfaces, DALTACs reconfigure the topology of multi-domain complexes through rational ligand selection and linker engineering. As a proof of concept, we designed JZY3032, the first-in-class AR-p300 DALTAC, to disable the androgen receptor (AR)-p300 transcriptional complex, a critical regulatory node in prostate cancer. Guided by iterative medicinal-chemistry optimization, we conjugated an AR LBD inhibitor to a selective p300 bromodomain inhibitor using a tunable linker optimized for cooperative, simultaneous dual engagement. The resulting construct redirects the physiological AR-p300 interaction surface into a sterically misaligned, non-productive configuration, thereby preventing AR N-terminal domain communication with p300 and suppressing enhancer activation. Mechanistic specificity was confirmed using two negative-control analogs that selectively disrupt AR or p300 binding; both lacked biological activity, demonstrating that dual engagement and domain-reconfiguration are required for DALTAC function. SAR studies revealed that linker length, rigidity, and exit-vector orientation are key determinants of complex miswiring efficiency. Functionally, JZY3032 potently inhibits growth of AR- and p300-co-dependent prostate cancer models while sparing AR-negative lineages, establishing the lineage-selective therapeutic potential arising from engineered domain miswiring. Collectively, these data establish DALTACs as a new class of proximity-based therapeutics capable of disabling oncogenic transcriptional complexes through topology engineering. JZY3032 exemplifies a broadly extensible, modular chemistry platform for rationally designing future DALTAC molecules targeting diverse disease-relevant protein assemblies.
利益披露 Disclosure
J. Yang, None..
S. Jin, None.