Expanding pharmacological modalities for targeted cancer therapy

项目总结/摘要 靶向癌症治疗需要完全和持续的药理学抑制各自的靶标， 由于在非酶癌症靶点中缺乏顺从位点， 转录因子沙利度胺类似物的临床成功证明， 促进靶向蛋白质降解可以克服这一局限性，提供一个新的药理学工具箱。最 小分子降解剂通过“分子胶”机制诱导新蛋白质-蛋白质相互作用， 桥接泛素E3连接酶和靶蛋白。在人类蛋白质组中存在超过600种泛素E3连接酶， 允许许多干预点调节它们的底物特异性以降解新底物，然而， 直接重新连接泛素连接酶以降解靶蛋白仍然具有挑战性;只有少数E3连接酶如CRBN， VHL和DCAF 15已被重新用于靶向蛋白质降解。为了制定总体战略 对于降解剂的发现，重要的是要全面了解化学物质如何降解， 配体促进新底物的降解。 最近描述的小分子BI-3802诱导BCL 6的快速泛素化和降解， 驱动弥漫性大B细胞淋巴瘤（DLBCL）的致癌转录因子。BI-3802降解BCL 6 治疗导致对DLBCL细胞的上级抗增殖作用，但其机制和分子机制 所涉及的机制仍然难以捉摸。 在这项拟议研究的F99阶段，Hojong Yoon将结合功能基因组学和 结构生物学方法剖析BI-3802诱导BCL 6降解的分子机制。 在这项拟议研究的K 00阶段，Hojong Yoon将利用他的新发现， 从F99-相聚合，以开发一种新的药理学干预方法。 拟议的工作将提供更好地了解小分子诱导的蛋白质降解， 目前小分子降解剂的优化和新目标降解剂的开发。 最终，这项研究的新见解将引领创新药理学的发展。 可以定制并应用于目前难治性癌症的模式。

Project Summary/Abstract Targeted cancer therapy requires complete and sustained pharmacological inhibition of the respective target, which is often challenging to achieve due to the lack of amenable sites in non-enzyme cancer targets such as transcription factors. The clinical success of thalidomide analogs demonstrates that small molecules that promote targeted protein degradation can overcome this limitation, providing a new pharmacologic toolbox. Most small molecule degraders induce new protein–protein interaction through a ‘molecular glue’ mechanism that bridges a ubiquitin E3 ligase and the target protein. Over 600 ubiquitin E3 ligases exist in the human proteome, allowing many points of intervention to tune their substrate specificity to degrade neo-substrates, However, directly re-wiring ubiquitin ligase to degrade target protein is still challenging; only few E3 ligases such as CRBN, VHL, and DCAF15 have been repurposed for targeted protein degradation. In order to devise general strategies for degrader discovery, it is important to acquire comprehensive mechanistic understanding of how chemical ligands facilitate the degradation of neo-substrates. A recently described small molecule, BI-3802 induces rapid ubiquitination and degradation of BCL6, an oncogenic transcription factor that drives diffuse large B cell lymphoma (DLBCL). BCL6 degradation by BI-3802 treatment results in superior anti-proliferative effects on DLBCL cells, but the mechanism and molecular machinery that are involved remain elusive. In the F99-phase of this proposed research, Hojong Yoon will use the combination of functional genomics and structural biology approaches to dissect the molecular mechanism of BI-3802-induced BCL6 degradation. In the K00-phase of this proposed research, Hojong Yoon will employ his new finding of chemically-inducible polymerization from the F99-phase to develop a novel method of pharmacological intervention. The proposed work will provide a better understanding of small molecule-induced protein degradation to enable the optimization of current small molecule degraders and the development of degraders for new targets. Ultimately, the new insights from this research will lead the development of innovative pharmacological modalities that can be tailored and applied to currently intractable cancers.