Discovery and Characterization of Active CBP/EP300 Degraders Targeting the HAT Domain,ACS Medicinal Chemistry Letters

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Discovery and Characterization of Active CBP/EP300 Degraders Targeting the HAT Domain
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2024-01-26 , DOI: 10.1021/acsmedchemlett.3c00490
Iván Cheng-Sánchez ₁ , Katherine A Gosselé _{1,

2} , Leonardo Palaferri ₁ , Mariia S Kirillova ₁ , Cristina Nevado ₁

Affiliation

Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that simultaneously bind an E3 ligase and a protein of interest, inducing degradation of the latter via the ubiquitin-proteasome system. Here we present the development of degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300)─two homologous multidomain enzymes crucial for enhancer-mediated transcription. Our PROTAC campaign focused on CPI-1612, a reported inhibitor of the histone acetyltransferase (HAT) domain of these two proteins. A novel asymmetric synthesis of this ligand was devised, while PROTAC-SAR was explored by measuring degradation, target engagement, and ternary complex formation in cellulo. Our study demonstrates that engagement of Cereblon (CRBN) and a sufficiently long linker between the E3 and CBP/EP300 binders (≥21 atoms) are required for PROTAC-mediated degradation using CPI-1612 resulting in a new active PROTAC dCE-1. Lessons learned from this campaign, particularly the importance of cell-based assays to understand the reasons underlying PROTAC performance, are likely applicable to other targets to assist the development of degraders.

中文翻译：

针对 HAT 域的活性 CBP/EP300 降解剂的发现和表征

蛋白水解靶向嵌合体 (PROTAC) 是双功能分子，可同时结合 E3 连接酶和目标蛋白质，通过泛素-蛋白酶体系统诱导后者降解。在这里，我们展示了针对 CREB 结合蛋白 (CBP) 和 E1A 相关蛋白 (EP300) 的降解剂的开发，这两种同源多域酶对于增强子介导的转录至关重要。我们的 PROTAC 活动重点关注 CPI-1612，据报道，这是这两种蛋白质的组蛋白乙酰转移酶 (HAT) 结构域的抑制剂。设计了该配体的新型不对称合成，同时通过测量纤维素中的降解、靶标接合和三元复合物形成来探索 PROTAC-SAR。我们的研究表明，使用 CPI-1612 进行 PROTAC 介导的降解需要 Cereblon (CRBN) 的接合以及 E3 和 CBP/EP300 结合物（≥21 个原子）之间足够长的连接基，从而产生新的活性 PROTAC dCE-1 。从这次活动中汲取的经验教训，特别是基于细胞的测定对于了解 PROTAC 性能背后原因的重要性，可能适用于其他目标，以协助降解剂的开发。

更新日期：2024-01-26

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