Abstract 4513: Exploration degradation of intrinsically disordered protein YAP induced by PROTACs

Abstract

Abstract Yes-associated protein (YAP), a potent oncogene and a key player in the Hippo tumor suppression pathway, has long been considered challenging to target due to its partially intrinsically disordered nature. However, recent advancements in High-throughput Screening (HTS) have yielded a breakthrough, as several YAP binders have been identified, igniting new possibilities in the quest to combat YAP-driven malignancies. Building upon this progress, a novel approach utilizing Proteolysis-Targeting Chimera (PROTAC) technology was employed to design and synthesize a series of YAP degraders. Here, our degraders were created by linking NSC682769, a previously reported YAP binder, with either VHL ligand 2 or pomalidomide using various linkers of different lengths and types. Among these degraders, YZ-6 emerges as the most promising, inducing rapid and sustained YAP degradation via promoting its ubiquitination-proteasome-dependent proteolysis. This process effectively suppressed YAP/TEAD-led transcription in both YAP-dependent NCI-H226 and Huh7 cancer cell lines. In addition to its degradation capabilities, YZ-6 also exhibited antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppressed tumor development in the Huh7 xenograft mouse model, accompanied by a remarkable decrease in YAP levels, without adverse effects on the mice. These findings highlight the potential of PROTAC-mediated degradation as a viable strategy for reducing oncogenic YAP levels and attenuating downstream signaling in cancer cells. Moreover, the development of PROTACs based on NSC672869 holds promise for treating YAP-driven malignancies, opening new avenues for cancer therapy. Citation Format: Chen Zhou, Chunbao Sun, Liya Pi, Chenglong Li. Exploration degradation of intrinsically disordered protein YAP induced by PROTACs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4513.