PO.BCS01.09 · 生物信息与计算

结构导向的EZH2与多巴胺D1受体双重靶向可抑制TNBC生长和转移

Structure-guided dual targeting of EZH2 and dopamine D1 receptor suppresses TNBC growth and metastasis

编号 1488 展板 27 时间 4/20 09:00–12:00 区域 Section 5 主讲 Francesco Drago, Unknown

分会场 Integrative Computational Approaches 1

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作者与单位 Authors & Affiliations

Francesco Drago¹, Libere Ndacayisaba², Xilal Y. Rima³, Gautam Sarathy¹, Deborah Ramsey⁴, Gwen Fewell⁴, Senthil Saravanamuthu², Sanjay Gupta⁵, Giovanni Nigita¹, Eduardo Reátegu³, Pierre Giglio⁶, Christian Rolfo¹, Eswar Shankar¹

¹Division of Medical Oncology, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH,²ONS BIO LLC, Cleveland, OH,³Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, Columbus, OH,⁴SYNVIVO INC., Huntsville, AL,⁵Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH,⁶9Department of Neurology, School of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH

摘要 Abstract

中文摘要

三阴性乳腺癌（TNBC）是一种侵袭性亚型，复发率高、治疗手段有限，这凸显了对基于机制的策略的需求。EZH2作为PRC2的催化亚基，驱动TNBC的增殖、转移和化疗耐药，而多巴胺D1受体（D1R）的激活可诱导凋亡、自噬并抑制侵袭。免疫组化证实EZH2高表达且H3K27me3升高，但由于其非酶功能，单纯的催化抑制并不充分。我们假设双重靶向EZH2和D1R可通过破坏EZH2-D1R轴协同抑制TNBC。使用全长AlphaFold EZH2结构和三种配体（GSK126、A77636、SKF38393）进行计算建模，通过PocketMiner和Fpocket识别经典和隐蔽结合口袋，揭示SET结构域为主要的高亲和力位点。DiffDock对接显示GSK126的稳定、高亲和力结合，而A77636和SKF38393则表现出动态、特异性较低的相互作用。历时100 ns的分子动力学模拟证实了GSK126的稳定性及其在关键残基（624、684、686）处的持续接触，提供了机制层面的洞见。免疫共沉淀验证了EZH2-D1R相互作用，D1R敲低降低了联合疗效。实验上，联合治疗降低了2D细胞活力（CI = 0.24）。在基于液滴的肿瘤球体（TSIMS）中，GSK126 + A77636使球体直径缩小62%，并诱导坏死而非凋亡，共聚焦成像显示EZH2降解、H3K27me3丢失和细胞骨架破坏。EZH2敲除细胞无法形成球体。在血管化的SynTumor器官芯片模型中，该联合方案在96小时内使循环肿瘤细胞减少50%，证明了对转移扩散的抑制。总之，这些计算导向和实验研究结果确立了一种可转化落地的双靶点策略，能够协同抑制TNBC的生长和转移。（由DOD资助：W81XWH2010065，Eswar Shankar。）

查看英文原文 English abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype with high relapse rates and limited therapies, emphasizing the need for mechanism-based strategies. EZH2, the catalytic subunit of PRC2, drives TNBC proliferation, metastasis, and chemoresistance, while dopamine D1 receptor (D1R) activation induces apoptosis, autophagy, and invasion inhibition. Immunohistochemistry confirmed strong EZH2 expression and elevated H3K27me3, but catalytic inhibition alone is insufficient due to non-enzymatic functions. We hypothesized that dual targeting of EZH2 and D1R would synergistically suppress TNBC by disrupting the EZH2-D1R axis. Computational modeling using a full-length AlphaFold EZH2 structure and three ligands (GSK126, A77636, SKF38393) identified canonical and cryptic binding pockets via PocketMiner and Fpocket, revealing the SET domain as the primary high-affinity site. DiffDock docking showed stable, high-affinity binding of GSK126, while A77636 and SKF38393 displayed dynamic, less-specific interactions. Molecular dynamics simulations over 100 ns confirmed GSK126's stability and persistent contacts at key residues (624, 684, 686), providing mechanistic insight. Immunoprecipitation validated an EZH2-D1R interaction, and D1R knockdown reduced combination efficacy. Experimentally, combination therapy reduced 2D cell viability (CI = 0.24). In droplet-based tumor spheroids (TSIMS), GSK126 + A77636 decreased spheroid diameter by 62% and induced necrosis without apoptosis, with confocal imaging showing EZH2 degradation, H3K27me3 loss, and cytoskeletal disruption. EZH2 knockout cells failed to form spheroids. In a vascularized SynTumor organ-on-chip model, the combination reduced circulating tumor cells by 50% within 96 hours, demonstrating suppression of metastatic spread. Together, these silico-guided and experimental findings establish a translationally actionable dual-target strategy that synergistically inhibits TNBC growth and metastasis. (Supported by DOD: W81XWH2010065, Eswar Shankar.).

利益披露 Disclosure

F. Drago, None.. L. Ndacayisaba, None.. X. Y. Rima, None.. G. Sarathy, None.. D. Ramsey, None.. G. Fewell, None.. S. Saravanamuthu, None.. S. Gupta, None.. G. Nigita, None.. E. Reátegu, None.. P. Giglio, None.. C. Rolfo, None.. E. Shankar, None.

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