Discovery of as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1.

Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader by employing autophagosome-tethering compound technology. Compound efficiently degraded DDR1 protein with a DC value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor . These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.