title: Discovery of MEK/PI3K dual inhibitor via structure-based virtual screening.
abstract: Mitogen/extracellular signal-regulated kinase (MEK) and phosphoinositide 3-kinase (PI3Kα) are considered to be promising targets for the development of anticancer therapeutics. We report the first example of the successful application of structure-based virtual screening to identify novel inhibitors of MEK with IC(50) values ranging from 1 to 25 μM. One of the four newly identified MEK inhibitors was found to be also a potent inhibitor of PI3Kα with submicromolar inhibitory activity (IC(50)=0.3 μM). Because this dual inhibitor was screened for having desirable physicochemical properties as a drug candidate as well as the high inhibitory activities against MEK and PI3Kα, it warrants further development through structure-activity relationship (SAR) studies to optimize the inhibitory and anticancer activities. Structural features relevant to the stabilization of the dual inhibitor in the ATP-binding sites of MEK1 and PI3Kα are addressed in detail.
authors: Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea. hspark@sejong.ac.kr
authors: Hwangseo
authors: H
authors: Park
authors: Soyoung
authors: S
authors: Lee
authors: Sungwoo
authors: S
authors: Hong
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors