具有增强选择性和降解起始的p300靶向降解物的开发。

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Graham P Marsh, Mark S Cooper, Sean Goggins, Stephen J Reynolds, Dean F Wheeler, Joel O Cresser-Brown, Robert E Arnold, Emily G Babcock, Gareth Hughes, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A Harrison, Christopher J Ott, Hannah J Maple
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引用次数: 0

摘要

p300和CBP是同源的表观遗传调控因子,被认为是癌症治疗的有希望的治疗靶点。到目前为止,小分子p300/CBP抑制剂无法区分这些密切相关的蛋白质,但为了探测它们不同的细胞功能,选择性是理想的。此外,在多种癌症中,CREBBP突变的功能丧失与p300建立了平行依赖的合成致死率,这可以通过选择性治疗剂来利用。为了解决这个问题,我们开发了靶向p300的异双功能降降剂,使用有效的基于螺旋-乙酰胆碱的抑制剂iP300w,通过p300的HAT结构域招募p300。铅降解剂BT-O2C在HAP1细胞中表现出更高的选择性和更快的起效,并且在CIC::DUX4肉瘤(CDS)细胞系(IC50 = 152-221 nM)中具有细胞毒性,显著降低CDS靶基因(ETV1, ETV4, ETV5)的表达。综上所述,我们的研究结果表明,BT-O2C代表了一种有用的工具降解剂,可以进一步探索p300的降解作为一种治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development of p300-targeting degraders with enhanced selectivity and onset of degradation.

p300 and CBP are paralogous epigenetic regulators that are considered promising therapeutic targets for cancer treatment. Small molecule p300/CBP inhibitors have so far been unable to differentiate between these closely related proteins, yet selectivity is desirable in order to probe their distinct cellular functions. Additionally, in multiple cancers, loss-of-function CREBBP mutations set up a paralog dependent synthetic lethality with p300, that could be exploited with a selective therapeutic agent. To address this, we developed p300-targeting heterobifunctional degraders that recruit p300 through its HAT domain using the potent spiro-hydantoin-based inhibitor, iP300w. Lead degrader, BT-O2C, demonstrates improved selectivity and a faster onset of action compared to a recently disclosed A 485-based degrader in HAP1 cells and is cytotoxic in CIC::DUX4 sarcoma (CDS) cell lines (IC50 = 152-221 nM), significantly reducing expression of CDS target genes (ETV1, ETV4, ETV5). Taken together, our results demonstrate that BT-O2C represents a useful tool degrader for further exploration of p300 degradation as a therapeutic strategy.

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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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