PO.CH01.01 · 化学

用于治疗SMARCA4突变型癌症的每月一次静脉给药及口服可生物利用的SMARCA2降解剂的发现与表征

Discovery and characterization of once in a month intravenous and orally bioavailable SMARCA2 degraders for treating SMARCA4 mutant cancers

编号 5175 展板 25 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, Kiran B. Aithal, Sandeep Vitthal Dukare, Charamanna KB, Khaji Abdul Rawoof, Prasath Kothandaraman, Amit A. Dhudashiya, Nandish C, Payel Das, Anuradha Gadeval, Madhu K L, Bhagwan Mahadeo Dhaytadak, Gopinath CH, T Jagadeesh Kumar, Suraj Tgore, 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）染色质重塑复合体是一个多亚基组装体，通过ATP依赖性核小体重新定位调控染色质可及性，从而调节转录、DNA重组与修复以及有丝分裂染色体分离。其催化活性由两个相互排斥的ATP酶介导，即SMARCA2（BRM）和SMARCA4（BRG1）。在SMARCA4缺陷型肿瘤中，致癌依赖性转移至残留的含SMARCA2的SWI/SNF复合体，从而形成一种合成致死脆弱性。这种依赖性已通过基因沉默研究得到验证，使SMARCA2成为SMARCA4突变型癌症中一个极具吸引力的治疗靶点。我们报告了基于合理设计的高效、选择性SMARCA2降解剂的鉴定和临床前开发，其设计通过优化SMARCA2/4溴结构域结合剂、降解决定子连接部分以及特定E3连接酶配体的组合而实现。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。合成了所选化合物并在多种细胞分析中进行评估，以评价其机制和功能结果。数种化合物表现出强效且选择性的SMARCA2降解，在一组SMARCA4突变型细胞系中引发独特的表型反应。先导静脉给药化合物在多个SMARCA4突变异种移植模型中以耐受良好的剂量展现出稳健的抗肿瘤疗效，并确认了靶标降解。该化合物的IND申请已获USFDA受理。制剂研究有助于鉴定出一种长效静脉制剂，该制剂在每4周给药一次后展现出显著疗效。随后的ADME优化产生了在受试物种间具有良好口服生物利用度的化合物。此外，该先导降解剂在多个SMARCA4缺陷型CDX模型中以耐受良好的剂量展现出稳健的抗肿瘤疗效。非啮齿类动物物种中的重复给药耐受性研究正在进行中，以支持在2025年第四季度提名候选药物。

查看英文原文 English abstract

The BAF (SWI/SNF) chromatin remodelling complex is a multi-subunit assembly that regulates chromatin accessibility via ATP-dependent nucleosome repositioning, thereby modulating transcription, DNA recombination & repair, and mitotic chromosome segregation. Its catalytic activity is mediated by two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1). In SMARCA4-deficient tumors, oncogenic dependency shifts to the residual SMARCA2-containing SWI/SNF complex, establishing a synthetic lethal vulnerability. This dependency has been validated through genetic silencing studies, positioning SMARCA2 as a compelling therapeutic target in SMARCA4-mutant cancers. We report the identification and preclinical development of highly potent and selective SMARCA2 degraders based on rational design by optimizing assemblies of SMARCA2/4 bromodomain binders, degron-linking moieties, and ligands for specific E3 ligases. Design prioritization was guided by our proprietary ternary complex modelling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders). Selected compounds were synthesized and evaluated across multiple cellular assays to assess mechanistic and functional outcomes. Several compounds demonstrated potent and selective SMARCA2 degradation, eliciting distinct phenotypic responses in a panel of SMARCA4-mutant cell lines. The lead IV compound demonstrated robust anti-tumor efficacy in multiple SMARCA4 mutant xenograft models with confirmed target degradation, at well tolerated doses. IND application was accepted by USFDA for this compound. Formulation efforts helped in identification of long-acting IV formulation which demonstrated significant efficacy following once in 4 weeks administration. Subsequent ADME optimization yielded compounds with favourable oral bioavailability across tested species. Furthermore, the lead degrader exhibited robust antitumor efficacy in multiple SMARCA4-deficient CDX models at well-tolerated doses. Repeat-dose tolerability studies in non-rodent species are ongoing to support candidate nomination by Q4 2025.

利益披露 Disclosure

B. Kuila, None.. K. B. Aithal, None.. S. V. Dukare, None.. C. Kb, None.. K. Abdul Rawoof, None.. P. Kothandaraman, None.. A. A. Dhudashiya, None.. N. C, None.. P. Das, None.. A. Gadeval, None.. M. K l, None.. B. Dhaytadak, None.. G. Ch, None.. T. Kumar, None.. S. Tgore, 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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