title: ROS1 Kinase Inhibitors for Molecular-Targeted Therapies.
abstract: 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.
authors.forename: M M
authors.initials: MM
authors.lastname: Al-Sanea
authors.forename: A Z
authors.initials: AZ
authors.lastname: Abdelazem
authors.forename: B S
authors.initials: BS
authors.lastname: Park
authors.forename: K H
authors.initials: KH
authors.lastname: Yoo
authors.forename: T
authors.initials: T
authors.lastname: Sim
authors.forename: Y J
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea. LSH6211@kist.re.kr.
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
mesh_terms: D002626:Chemistry, Pharmaceutical; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human