PO.CH01.01 · 化学

选择性降解SMARCA4作为SMARCA4驱动型癌症的治疗策略

Selective degradation of SMARCA4 as a therapeutic strategy in SMARCA4 driven cancers

编号 5176 展板 26 时间 4/21 09:00–12:00 区域 Section 39 主讲 Susanta Samajdar, PhD

分会场 Targeted Protein Degradation and Induced Proximity

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作者与单位 Authors & Affiliations

Bilash Kuila, Sandeep Dukare, Kiran Aithal B, Charamanna KB, Khaji Abdul Rawoof, Amit A. Dhudashiya, Nandish C, karthik S, Payel Das, Gopinath CH, Suraj Tgore, Gauri Rahul Petkar, Mohamad Fairus Bin Abdul Kadir, Leena Khare, Ranadeep Bokalial, Samiulla DS, Subhendu Mukherjee, Saravanan Thiyagarajan, Kavitha Nellore, Rajesh Eswarappa, Girish Daginakatte, Chandrasekhar Abbineni, Sanjeev Giri, Murali Ramachandra, Susanta Samajdar

Aurigene Oncology Limited, Bangalore, India

摘要 Abstract

中文摘要

BAF（SWI/SNF）染色质重塑复合体调控核小体定位和DNA可及性，影响转录、重组、修复以及有丝分裂染色体解连环。它含有两个相互排斥的ATP酶，即SMARCA2（BRM）和SMARCA4（BRG1）。SMARCA4在多种癌症中频繁过表达，并与侵袭性表型和不良预后相关。SMARCA4的基因敲低可降低增殖并使肿瘤对化疗药物敏感，从而验证了SMARCA4作为治疗靶点的地位。SMARCA4与PTEN之间的合成致死性进一步支持了其临床相关性。在此，我们利用异双功能分子（将SMARCA2/4溴结构域抑制剂与E3连接酶配体相结合）开发了一种同类首创的SMARCA4选择性降解剂。设计优先级排序由我们专有的三元复合物建模算法ALMOND（新底物降解剂建模算法）指导。基于合理设计探索了多种连接子化学结构和出射向量，最终获得在多种癌细胞系中具有良好抗增殖活性的选择性SMARCA4降解剂。先导化合物在血液系统和前列腺癌模型中展现出强效的抗增殖作用，而SMARCA4突变型细胞系则表现出极低的敏感性，证实了靶标依赖性。初步的耐受性和疗效研究支持了SMARCA4降解的治疗潜力。这些发现为通过靶向蛋白降解来靶向SMARCA4确立了概念验证，作为一种治疗SMARCA4驱动型癌症、且具有改善安全窗口的新策略。更深入的体内研究正在进行中，以在2026年第一季度完成候选药物提名。

查看英文原文 English abstract

The BAF (SWI/SNF) chromatin remodelling complex regulates nucleosome positioning and DNA accessibility, influencing transcription, recombination, repair, and mitotic chromosome decatenation. It contains two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1). SMARCA4 is frequently overexpressed in several cancers and is associated with aggressive phenotypes and poor prognosis. Genetic knockdown of SMARCA4 reduces proliferation and sensitizes tumors to chemotherapeutics, validating SMARCA4 as a therapeutic target. Synthetic lethality between SMARCA4 and PTEN further supports its clinical relevance. Here, we developed a first-in-class SMARCA4-selective degrader using hetero-bifunctional molecules that combine SMARCA2/4 bromodomain inhibitors with E3 ligase ligands. Design prioritization was guided by our proprietary ternary complex modelling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders). Multiple linker chemistries and exit vectors were explored based on rational designs which resulted in selective SMARCA4 degraders with good anti-proliferative activity in multiple cancer cell lines. Lead compound exhibited potent anti-proliferative effects in hematological and prostate cancer models, while SMARCA4-mutant cell lines showed minimal sensitivity, confirming target dependency. Preliminary tolerability and efficacy studies support the therapeutic potential of SMARCA4 degradation. These findings establish proof-of-concept for targeting SMARCA4 via targeted protein degradation as a novel strategy for treating SMARCA4-driven cancers with improved safety margin. Advanced in-vivo studies are in progress to complete candidate nomination by Q1 2026

利益披露 Disclosure

K. Aithal B, None.. C. Kb, None.. K. Rawoof, None.. A. Dhudashiya, None.. N. C, None.. K. S, None.. P. Das, None.. G. Ch, None.. S. Tgore, None.. G. Rahul Petkar, None.. M. Bin Abdul Kadir, None.. L. Khare, None.. R. Bokalial, None.. S. Ds, None.. S. Mukherjee, None.. S. Thiyagarajan, None.. K. Nellore, None.. R. Eswarappa, None.. G. Daginakatte, None.. C. Abbineni, None.. S. Giri, None.. M. Ramachandra, None.. S. Samajdar, None.

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