Discovery of highly selective, orally available small-molecule DDR1 inhibitors that reprogram the collagen-DDR1 tumor microenvironment

DDR1 (Discoidin domain receptor 1) is a collagen-activated receptor that facilitates tumor growth by orchestrating extracellular matrix (ECM) remodeling, pro-survival signaling, epithelial-mesenchymal transition (EMT), metastasis, and immune exclusion. Interactions between collagen and DDR1 generate a tightly organized matrix that restricts T-cell infiltration and promotes CAF-mediated desmoplasia, leading to immune-cold tumor microenvironments. Inhibition of DDR1 remodels the extracellular matrix, suppresses AKT/MAPK/NF-κB signaling pathways, eliminates cancer stemness, and disrupts tumor-stroma interactions, thereby enhancing immune infiltration and significantly improving the efficacy of PD-1/PD-L1 blockade. Collectively, these features establish DDR1 as an ideal therapeutic target in ECM-abundant malignancies, including PDAC, TNBC, and NSCLC. Employing a non-kinase scaffold-hopping approach combined with fragment-based drug discovery, we developed a selective series of Type II, DFG-out state-specific DDR1 inhibitors (CVD series). Lead optimization generated sub-10 nM compounds with high potency and excellent selectivity. In collaboration with structural biologists, we solved DDR1-CVD co-crystal structures and elucidated their binding mechanism using synchrotron X-ray crystallography. Our inhibitors act as Type II, DFG-out state-specific binders, occupying a previously unexploited pocket in DDR1. This poster describes the discovery, structural validation, and optimization of a novel, lead-stage selective DDR1 inhibitor.