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小分子诱导的聚合反应可引发BCL6降解
2020-11-22 23:44

美国丹娜-法伯癌症研究所Benjamin L. Ebert、Eric S. Fischer等研究人员合作发现,小分子诱导的聚合反应可引发BCL6降解。该项研究成果于2020年11月18日在线发表在《自然》杂志上。

研究人员报告了靶向蛋白质降解的另一种机制,即一个小分子诱导目标蛋白质的高度特异性可逆聚合,随后将其螯合成细胞聚集并降解。BI-3802是一种小分子,可与致癌转录因子B细胞淋巴瘤6(BCL6)的BTB(Broad-complex, Tramtrack and Bric-à-brac)结构域结合,并导致BCL66的蛋白酶体降解。研究人员使用冷冻电镜揭示了BCL6结合分子的溶剂暴露部分如何促进复合配体-蛋白质表面,这导致BCL6同源二聚体形成超分子结构。药物诱导的BCL6纤维形成促进了SIAH1 E3泛素连接酶介导的泛素化。
 
这些发现表明,诸如BI-3802之类的小分子可以诱导聚合反应,并伴随高度特异性的蛋白质降解;与其他BCL6抑制剂诱导的作用相比,在BCL6的情况下,其药理活性增强。这些发现为治疗剂和合成生物学的发展开辟了新途径。
 
据悉,有效和持续抑制非酶致癌驱动蛋白是主要的药学挑战。沙利度胺类似物的临床成功证明了药物诱导转录因子和其他癌症靶标降解的治疗功效,但是使用现有方法相当一部分蛋白质对靶向降解具有抵抗力。
 
附:英文原文

Title: Small-molecule-induced polymerization triggers degradation of BCL6

Author: Mikoaj Sabicki, Hojong Yoon, Jonas Koeppel, Lena Nitsch, Shourya S. Roy Burman, Cristina Di Genua, Katherine A. Donovan, Adam S. Sperling, Moritz Hunkeler, Jonathan M. Tsai, Rohan Sharma, Andrew Guirguis, Charles Zou, Priya Chudasama, Jessica A. Gasser, Peter G. Miller, Claudia Scholl, Stefan Frhling, Radosaw P. Nowak, Eric S. Fischer, Benjamin L. Ebert

Issue&Volume: 2020-11-18

Abstract: Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets1,2,3, but a substantial subset of proteins are resistant to targeted degradation using existing approaches4,5. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL66. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand–protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.

DOI: 10.1038/s41586-020-2925-1

Source: https://www.nature.com/articles/s41586-020-2925-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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