Vectorized ULK1/2 and VPS34 Inhibitors for Tissue-Selective Autophagy Inhibition in Oncology.

Autophagy, the primary lysosomal degradation pathway, plays a key role in cell survival and homeostasis. In tumors, it is upregulated to support cancer cell plasticity, adaptation to the microenvironment, and therapy resistance, making its inhibition an attractive therapeutic strategy. However, since autophagy is essential in healthy tissues, selective inhibition in tumors is critical. To address this, we designed inhibitors of two autophagy initiation factors (ULK1/2 and VPS34) equipped with tumor-targeting vectors. Our most promising candidates combine a low-nanomolar ULK1/2 inhibitory scaffold with an RGR-sequence targeting peptide. These compounds were validated across in vitro, in cellulo, and in vivo models, demonstrating selective activity and preserved efficacy. As the first examples of tumor-targeted autophagy inhibitors, they open new avenues for developing tissue-specific modulators of autophagy, with potential applications in oncology and beyond.