DDR1-targeted therapies: current limitations and future potential

Drug Discov Today. 2024 May;29(5):103975. doi: 10.1016/j.drudis.2024.103975. Epub 2024 Apr 4.

Abstract

Discoidin domain receptor (DDR)-1 has a crucial role in regulating vital processes, including cell differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. Overexpression or activation of DDR1 in various pathological scenarios makes it a potential therapeutic target for the treatment of cancer, fibrosis, atherosclerosis, and neuropsychiatric, psychiatric, and neurodegenerative disorders. In this review, we summarize current therapeutic approaches targeting DDR1 from a medicinal chemistry perspective. Furthermore, we analyze factors other than issues of low selectivity and risk of resistance, contributing to the infrequent success of DDR1 inhibitors. The complex interplay between DDR1 and the extracellular matrix (ECM) necessitates additional validation, given that DDR1 might exhibit complex and synergistic interactions with other signaling molecules during ECM regulation. The mechanisms involved in DDR1 regulation in cancer and inflammation-related diseases also remain unknown.

Keywords: DDR1; fibrosis; targeted therapy; tumor immunity.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Discoidin Domain Receptor 1* / antagonists & inhibitors
  • Discoidin Domain Receptor 1* / metabolism
  • Extracellular Matrix / metabolism
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasms* / drug therapy
  • Signal Transduction / drug effects

Substances

  • Discoidin Domain Receptor 1
  • DDR1 protein, human