A Dual-Target and Dual-Mechanism\nDesign Strategy by\nCombining Inhibition and Degradation Together

Glioblastoma,\na highly aggressive brain tumor, lacks\neffective\ntreatment with low 5 year survival rates. Urgency for new therapies\nis evident. Mammalian targets of rapamycin (mTOR) and G1 to S phase\ntransition 1 gene (GSPT1) are overexpressed in glioblastoma, regulating\nvital cellular functions. Current mTOR inhibitors face challenges\nin clinical efficacy and drug resistance. Similarly, GSPT1-targeting\ntherapies have not progressed of glioblastoma in clinical trials.\nResearch studies suggested that combining mTOR inhibition with GSPT1\ndegradation may overcome resistance and enhance efficacy. We propose\nthe concept of jointly implementing inhibition and degradation on\ndifferent proteins, integrating the properties of inhibitors and degraders\ninto the same molecule. Introducing YB-3–17, a novel bifunctional\nmolecule, robustly inhibits mTOR and selectively degrades GSPT1. As\na tool compound for proof-of-concept studies, YB-3–17 sharpens\nselectivity, avoiding off-target effects, and selectively induces\nGSPT1 degradation and mTOR inhibition, showing superior efficacy in\ntumor cell lines compared to that of standalone therapies. RNA-seq\nanalysis highlights the advantages of YB-3-17 over mTOR inhibitor\ntreatment. YB-3–17 can safely and effectively inhibit tumor\ngrowth\nin mice, offering a promising direction for precision treatment of\nglioblastoma, representing the first attempt to combine mTOR inhibition\nwith GSPT1 degradation. This work also demonstrates that it is conceptually\npossible to successfully combine the properties of small molecule\ninhibitors and degraders into a single molecule, killing two birds\nwith one stone.