Small-molecule-induced polymerization triggers degradation of BCL6.
Small-molecule-induced polymerization triggers degradation of BCL6.
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DOI：
10.1038/s41586-020-2925-1
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发表时间：
2020-12
期刊：
影响因子：
64.8
通讯作者：
Ebert BL
中科院分区：
文献类型：
--
作者：
Słabicki M;Yoon H;Koeppel J;Nitsch L;Roy Burman SS;Di Genua C;Donovan KA;Sperling AS;Hunkeler M;Tsai JM;Sharma R;Guirguis A;Zou C;Chudasama P;Gasser JA;Miller PG;Scholl C;Fröhling S;Nowak RP;Fischer ES;Ebert BL
有效和持续地抑制非酶致癌驱动蛋白是一个重大的药理学挑战。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点降解的治疗效果，但使用目前的方法，有相当一部分蛋白质对靶向蛋白质降解具有抵抗力。在这里，我们报告了另一种机制，通过这种机制，小分子诱导高度特异的可逆聚合，隔离到细胞焦点，并随后降解目标蛋白。BI-3802是一个小分子，它结合致癌转录因子BCL6的BTB结构域，导致蛋白酶体降解。我们使用冷冻EM来揭示BCL6抑制剂在溶剂中的部分是如何作用于与BCL6同源二聚体结合形成超分子结构的复合配体/蛋白质表面的。药物诱导的BCL6丝的形成促进了SIAH1 E3泛素连接酶的泛素化。我们的发现表明，一个小分子可以诱导聚合与高度特异的蛋白质降解相结合，这在BCL6的情况下导致了优越的药理活性。这些发现为治疗学和合成生物学的发展开辟了新的途径。
Effective and sustained inhibition of non-enzymatic oncogenic driver proteins represents a major pharmacologic challenge. The clinical success of thalidomide analogs demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets, but a significant subset of proteins are recalcitrant to targeted protein degradation using current approaches. Here we report an alternative mechanism, whereby a small molecule induces highly specific, reversible polymerization, sequestration into cellular foci, and subsequent degradation of a target protein. BI-3802 is a small molecule that binds the BTB domain of the oncogenic transcription factor BCL6 and results in proteasomal degradation. We used cryo-EM to reveal how the solvent-exposed moiety of a BCL6 inhibitor 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 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to superior pharmacological activity. These findings create new avenues for the development of therapeutics and synthetic biology.