ROS1 is a pivotal transmembrane receptor protein tyrosine kinase which regulates several cellular
processes like apoptosis, survival, differentiation, proliferation, cell migration, and transformation. There is
increasing evidence supporting that ROS1 plays an important role in different malignancies including
glioblastoma, colorectal cancer, gastric adenocarcinoma, inflammatory myofibroblastic tumor, ovarian cancer,
angiosarcoma, and non small cell lung cancer; thus, ROS1 has become a potential drug discovery target.
ROS1 shares about 49% sequence homology with ALK primary structure; therefore, wide range of ALK
kinase inhibitors have shown in vitro inhibitory activity against ROS1 kinase. After Crizotinib approval by
FDA for the management of ALK-rearranged lung cancer, ROS1-positive tumors have been focused. Although
significant advancements have been achieved in understanding ROS1 function and its signaling pathways
plus recent discovery of small molecules modulating ROS1 protein, a vital need of medicinal chemistry
efforts is still required to produce selective and potent ROS1 inhibitors as an important therapeutic strategy
for different human malignancies. This review focuses on the current knowledge about different scaffolds targeting
ROS1 rearrangements, methods to synthesis, and some biological data about the most potent compounds
that have delivered various scaffold structures.