The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

Int J Mol Sci. 2021 Jun 18;22(12):6535. doi: 10.3390/ijms22126535.

Abstract

Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

Keywords: DDR1 and DDR2; cancer; discoidin domain receptor (DDR); kinase inhibitors; structure-activity relationship (SAR).

Publication types

  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Biomarkers, Tumor
  • Discoidin Domain Receptor 1 / antagonists & inhibitors*
  • Discoidin Domain Receptor 1 / chemistry
  • Discoidin Domain Receptor 1 / metabolism
  • Discoidin Domain Receptor 2 / antagonists & inhibitors*
  • Discoidin Domain Receptor 2 / chemistry
  • Discoidin Domain Receptor 2 / metabolism
  • Disease Management
  • Disease Susceptibility
  • Drug Design
  • Humans
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / metabolism
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / etiology
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Structure-Activity Relationship

Substances

  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • DDR1 protein, human
  • DDR2 protein, human
  • Discoidin Domain Receptor 1
  • Discoidin Domain Receptor 2