Exploring Degradation of Intrinsically Disordered Protein YAP induced by PROTACs
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 advances in High-throughput Screening (HTS) have led to the discovery of a few YAP binders. 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. The most promising degrader YZ-6 recruits the E3 ligase VHL, inducing rapid and sustained YAP degradation leading to suppression of 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 potent antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppresses tumor development in the Huh7 xenograft mouse model 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.