An updated review of discoidin domain receptor 1 (DDR1) modulators (2020-present)

As a unique collagen-activated receptor tyrosine kinase, discoidin domain receptor 1 (DDR1) mediates signaling essential for cell proliferation, survival, adhesion, and matrix remodeling. Conversely, its dysregulation is implicated in cancer, tissue fibrosis, atherosclerosis, and other inflammatory diseases. Emerging research reveals that the non-catalytic functions of DDR1 are critically involved in tumor progression, metastasis, and immune exclusion. Selectively inhibiting the catalytic and/or non-catalytic functions of DDR1 presents a promising therapeutic strategy for various diseases.

This article summarizes current progress on the development of inhibitors, degraders and biomolecules targeting DDR1 and their potential therapeutic application during the period from 2020 to 2025.

Significant efforts have been made to develop small-molecule DDR1 kinase inhibitors, yet achieving high selectivity remains a challenge. Degraders have been developed to inhibit both its catalytic and noncatalytic functions. Although these molecules offer conceptual advantages over traditional kinase inhibitors, they suffer from suboptimal pharmacokinetic properties. Alternatively, biologics such as antibodies and peptides can block the DDR1-collagen interaction, specifically inhibiting non-catalytic signaling, and one antibody is currently under clinical evaluation. Moving forward, the development of highly selective inhibitors and improvement of pharmacokinetic profiles for degraders will be pivotal for translating DDR1 targeting into viable therapies.