title: Talin Modulation by a Synthetic N-Acylurea Derivative Reduces Angiogenesis in Human Endothelial Cells.
abstract: Talin is a focal adhesion protein that activates integrins and recruits other focal adhesion proteins. Talin regulates the interactions between integrins and the extracellular matrix, which are critical for endothelial cells during angiogenesis. In this study, we successfully synthesized a novel talin modulator,N-((2-(1H-indol-3-yl)ethyl)carbamoyl)-2-(benzo[d][1,3]dioxol-5-yloxy)acetamide, referred to as KCH-1521. KCH-1521 was determined to bind talin and modulate downstream signaling molecules of talin. After 24 h of treatment, KCH-1521 changed the cell morphology of human umbilical vein endothelial cells (HUVECs) and reduced focal adhesion protein expression including vinculin and paxillin. Talin downstream signaling is regulated via focal adhesion kinase (FAK), kinase B (AKT), and extracellular signal-regulated kinase (ERK) pathways, however, treatment with KCH-1521 decreased phosphorylation of FAK, AKT, and ERK, leading to reduction of cell proliferation, survival, and angiogenesis. Interestingly, the expression of various angiogenic genes was significantly decreased after treatment with KCH-1521. Also, in vitro tube forming assay revealed that KCH-1521 reduced angiogenic networks in a time-dependent manner. To investigate the reversibility of its effects, KCH-1521 was removed after treatment. HUVECs recovered their morphology through rearrangement of the cytoskeleton and the expression of angiogenic genes was also recovered. By further optimization and in vivo studies of KCH-1521, a novel drug of talin modulation could be used to achieve therapeutic anti-angiogenesis for vascular diseases and cancers.
authors.affiliation: Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul 02841, Korea. irang.lim@gmail.com.
authors.forename: I-Rang
authors.initials: IR
authors.lastname: Lim
authors.affiliation: Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul 02841, Korea. drjoohj@gmail.com.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Joo
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. dha66@naver.com.
authors.forename: Minseon
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul 02841, Korea. mecey@naver.com.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul 02841, Korea. choisc86@gmail.com.
authors.forename: Seung-Cheol
authors.initials: SC
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Korea University, Seoul 02841, Korea. chungho@korea.ac.kr.
authors.forename: Chungho
authors.initials: C
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. jungj@knu.ac.kr.
authors.forename: Jong-Wha
authors.initials: JW
authors.lastname: Jung
authors.affiliation: Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul 02841, Korea. psyche94@gmail.com.
authors.forename: Soon Jun
authors.initials: SJ
authors.lastname: Hong
mesh_terms: D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D016608:Talin / Q000378:metabolism*; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016608:Talin; D014508:Urea
keywords: KCH-1521; anti-angiogenesis; focal adhesion; talin; talin modulator