Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Discoidin domain receptor 1 (DDR1) is implicated in cancer progression, metastasis, and immune exclusion.
• Existing DDR1 kinase inhibitors do not address the receptor's critical noncatalytic functions.
• Targeting DDR1 degradation offers a novel therapeutic strategy to block its oncogenic roles.

Purpose of the Study:

• To discover and characterize a novel compound capable of degrading DDR1.
• To investigate the therapeutic potential of targeting DDR1 noncatalytic functions through degradation.
• To evaluate the efficacy of the novel DDR1 degrader against cancer cell phenotypes.

Main Methods:

• Autophagosome-tethering compound technology was employed to discover DDR1 degraders.
• Compound LLC355's efficacy in degrading DDR1 protein was assessed in non-small cell lung cancer cells (NCI-H23).
• Mechanistic studies elucidated the pathway of DDR1 degradation, involving lysosome-mediated autophagy.

Main Results:

• Compound LLC355 demonstrated efficient DDR1 degradation with a DC50 of 150.8 nM.
• LLC355 induced DDR1 degradation via lysosome-mediated autophagy.
• LLC355 significantly suppressed cancer cell tumorigenicity, migration, and invasion, outperforming a known inhibitor.

Conclusions:

• LLC355 is a potent DDR1 degrader with therapeutic potential in cancer.
• Targeting DDR1 noncatalytic functions via degradation offers advantages over kinase inhibition.
• This study highlights a promising new avenue for cancer drug development by targeting DDR1 degradation.