Discovery of Novel PDEδ Autophagic Degraders: A Case Study of Autophagy-Tethering Compound (ATTEC).

The autophagy-tethering compound (ATTEC) technology has emerged as a promising strategy for targeted protein degradation (TPD). Here, we report the discovery of the first generation of PDEδ autophagic degraders using an ATTEC approach. The most promising compound 12c exhibited potent PDEδ binding affinity and efficiently induced PDEδ degradation in a concentration-dependent manner. Mechanistic studies confirmed that compound 12c reduced the PDEδ protein level through lysosome-mediated autophagy without affecting the PDEδ mRNA expression. Importantly, compound 12c was much more effective in suppressing the growth in KRAS mutant pancreatic cancer cells than the corresponding PDEδ inhibitor. Taken together, this study expands the application scope of the ATTEC approach and highlights the effectiveness of the PDEδ autophagic degradation strategy in antitumor drug discovery.