title: Discovery of Dual Inhibitors for Wild Type and D816V Mutant of c-KIT Kinase through Virtual and Biochemical Screening of Natural Products.
abstract: Although stem cell factor receptor (c-KIT) kinase is responsible for various malignant human cancers, the presence of constitutively active gain-of-function mutants has made it difficult to discover new anticancer agents using c-KIT as the target protein. To identify the common inhibitors of wild-type c-KIT and the most abundant gain-of-function mutant (D816V), the virtual screening of natural products was performed for the two target proteins in parallel with the scoring function improved by implementing a sophisticated solvation free energy term. As a result, four common inhibitors of natural origin are found with biochemical potencies ranging from low micromolar to submicromolar levels. The results of extensive docking simulations show that although the natural-product inhibitors establish weaker hydrophobic interactions with the D816V mutant than with the wild type, they exhibit a little higher inhibitory activity for the former than the latter by strengthening the hydrogen-bond interactions to a sufficient extent. Of the four natural-product inhibitors, (Z)-6-hydroxy-2-(4-methoxybenzylidene)benzofuran-3(2H)-one (3) is anticipated to serve as a new molecular core for the structure-activity relationship studies to optimize the biochemical potencies because it exhibits good inhibitory activity against both the wild type and D816V mutant despite its low molecular weight (268.3 amu).
authors.affiliation: Department of Bioscience and Biotechnology & Institute of Anticancer Medicine Development, Sejong University , 209 Neungdong-ro, Kwangjin-gu, Seoul 143-747, Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS) & Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS) & Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D009154:Mutation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000608903:(Z)-6-hydroxy-2-(4-methoxybenzylidene)benzofuran-3(2H)-one; D000970:Antineoplastic Agents; D001572:Benzofurans; D001688:Biological Products; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit