Abstract
In tumors, autophagy acts as a survival mechanism that protects tumor cells from cytotoxic drugs and the hypoxic and nutrient-deprived tumor microenvironment. Inhibition of autophagy has been shown to increase and restore sensitivity to cytotoxic therapy and to promote tumor cell death, both in vitro and in vivo. Recently, there is also evidence that autophagy plays a critical role in tumoral angiogenesis and lymphangiogenesis. To date, only the weak, non-specific autophagy inhibitor chloroquine is clinically used in oncology. Other, more specific autophagy blockers have been reported, e.g. inhibitors of the autophagy kinases ULK1/2 and Vps34. While potent in vitro, clinical translation is difficult: obtaining reproducible autophagy inhibition in vivo is challenging with these agents. This sets the stage for this project, which aims to prepare and investigate the following 2 novel compound types: 1) ULK1/2 and Vps34 PROTACs. These compounds could be especially efficient at inhibiting autophagy because they clear ULK1/2 or Vps34 from the cytosol: this not only abrogates their kinase activities, but also additional functionality that is exerted through protein-protein interactions. 2) Tumor-selective kinase inhibitors and PROTACs. Selective delivery of autophagy inhibitors to tumors would allow both intratumoral accumulation of the molecules and reduce exposure of healthy tissue. To this end, we will prepare peptide-drug conjugates of ULK1/2 and Vps34 inhibitors and PROTACs.
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