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 targets1-3, 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.

中文翻译：

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小分子诱导聚合引发 BCL6 降解

对非酶促致癌驱动蛋白的有效和持续抑制是一个主要的药理学挑战。沙利度胺类似物的临床成功证明了药物诱导的转录因子和其他癌症靶标降解的治疗功效 1-3，但相当一部分蛋白质对使用现有方法的靶向降解具有抗性 4,5。在这里，我们报告了靶向蛋白质降解的另一种机制，其中小分子诱导目标蛋白质的高度特异性、可逆聚合，然后将其隔离到细胞病灶中并随后降解。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 Broad-complex、Tramtrack 和 Bric-à-brac (BTB) 结构域结合，并导致 BCL66 的蛋白酶体降解。我们使用冷冻电子显微镜来揭示 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，该表面与 BCL6 同源二聚体结合形成超分子结构。药物诱导的 BCL6 细丝形成促进了 SIAH1 E3 泛素连接酶的泛素化。我们的研究结果表明，像 BI-3802 这样的小分子可以诱导聚合反应与高度特异性的蛋白质降解相结合，在 BCL6 的情况下，与其他 BCL6 抑制剂诱导的作用相比，这会导致药理活性增加。这些发现为治疗药物和合成生物学的开发开辟了新的途径。