Abstract 394: Bridged proteolysis targeting chimera (PROTAC) enables degradation of the cyclin D undruggable protein

Abstract Proteolysis targeting chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While significant progress has been made in developing PROTACs for various protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins lacking small-molecule binders. To overcome this limitation, we present a novel PROTAC approach, termed bridged PROTAC. This approach utilizes a small-molecule binder of the target protein’s binding partner to recruit the protein complex into proximity with an E3 ubiquitin ligase, enabling the degradation of the target undruggable protein. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1. MS28 effectively degraded cyclin D1 prior to CDK4/6 and with superior degradation potency through recruiting the CDK4/6-cyclin D1 complex to the von Hippel-Lindau (VHL) E3 ligase. MS28 suppressed the proliferation of lung and breast cancer cells more effectively than CDK4/6 inhibitor and degraders. Notably, while triple negative breast cancer (TNBC) cell lines were mostly insensitive to CDK4/6 inhibitor and degrader treatment, they exhibited potent sensitivity to MS28. RNA-sequencing analysis revealed that while MS28 and CDK4/6 inhibitor and degrader shared downregulated genes associated with cell cycle regulation and DNA replication, MS28 upregulated a unique set of genes such as those involved in the unfolded protein response and endoplasmic reticulum stress pathway. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins, thereby offering invaluable chemical tools for the study of these proteins, and potentially delivering greater therapeutic efficacy than small-molecule inhibitors or degraders targeting alternative components within the signaling pathway. Citation Format: Yue Zhong, Yan Xiong, Hyerin Yim, Xiaobao Yang, Kwang-Su Park, Ling Xie, Poulikos Poulikakos, Xian Chen, Jing Liu, Jian Jin. Bridged proteolysis targeting chimera (PROTAC) enables degradation of the cyclin D undruggable protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 394.