The bromodomain and extra-terminal (BET) family of proteins (BRD2, 3, 4 and T) has been the focus of an emerging paradigm in drug mechanism of action, whereby a drug is designed to trigger the proteolytic degradation of the target protein. The current design of protein degraders is typically based on bivalent molecules consisting of a ligand for the target protein and a ligand for a ubiquitin ligase (such as VHL, CRBN or XIAP). The degrader causes the association of the target protein with the E3 ubiquitin ligase and its subsequent ubiquitination and degradation. Due to their bivalent design such drugs typically have a higher molecular weight than classic small molecule drugs and may present some non-ideal properties as drugs. An alternative strategy for designing drugs that act through the degradation of the target protein is exemplified by the group of drugs termed SERDs (selective estrogen receptor degraders), for example fulvestrant. The molecular structures of SERDs are typically designed around an estrogen receptor ligand and a “degradation tail”, whose presence results in the degradation of the estrogen receptor. We will discuss the development of GNE-0011, which represents a novel class of monovalent BRD4 degrader that uses a “degradation tail” strategy.

Citation Format: Robert A. Blake. GNE-0011, a novel monovalent BRD4 degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4452.