Vulpetti Anna, Holzer Philipp, Schmiedeberg Niko, Imbach-Weese Patricia, Pissot-Soldermann Carole, Hollingworth Gregory J, Radimerski Thomas, Thoma Claudio R, Stachyra Therese-Marie, Wojtynek Matthias, Maschlej Magdalena, Chau Suzanne, Schuffenhauer Ansgar, Fernández César, Schröder Martin, Renatus Martin
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel 4002, Switzerland.
Oncology Drug Discovery, Novartis Institutes for BioMedical Research, Basel 4002, Switzerland.
ACS Med Chem Lett. 2023 Jun 2;14(7):949-954. doi: 10.1021/acsmedchemlett.3c00104. eCollection 2023 Jul 13.
In this study, we describe the rapid identification of potent binders for the WD40 repeat domain (WDR) of DCAF1. This was achieved by two rounds of iterative focused screening of a small set of compounds selected on the basis of internal WDR domain knowledge followed by hit expansion. Subsequent structure-based design led to nanomolar potency binders with a clear exit vector enabling DCAF1-based bifunctional degrader exploration.
在本研究中，我们描述了对DCAF1的WD40重复结构域（WDR）的强效结合剂的快速鉴定。这是通过两轮迭代聚焦筛选实现的，筛选基于内部WDR结构域知识选择的一小部分化合物，随后进行命中物扩展。后续基于结构的设计产生了具有明确离去向量的纳摩尔效价结合剂，从而能够探索基于DCAF1的双功能降解剂。
