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.

Identification of TLN1 as a prognostic biomarker to effect cell proliferation and differentiation in acute myeloid leukemia

“…Studies have shown that Talin is an indispensable factor for endothelial cell-mediated angiogenesis [14]. In patients with multiple myeloma and chronic lymphocytic leukemia, Talin1 can also promote the abnormal transport of malignant B cells to the bone marrow and lymph nodes by regulating α4β1 integrin activity.…”

Identification of TLN1 as a prognostic biomarker to effect cell proliferation and differentiation in Acute Myeloid Leukemia

“…The protein Talin1 encoded by TLN1 is a focal adhesion cytoskeleton protein that binds and activates integrins, and integrins recruit other focal adhesion kinases (FAKs). Studies have shown that Talin is an indispensable factor for endothelial cell-mediated angiogenesis 14 . In patients with multiple myeloma and chronic lymphocytic leukemia, Talin1 can also promote the abnormal transport of malignant B cells to the bone marrow and lymph nodes by regulating α4β1 integrin activity.…”

Myofibroblast differentiation is governed by adhesion mechanics, and inhibition of Talin2 reverses lung and kidney fibrosis

“…To our knowledge, the only method of targeting talin other than siRNA is the small molecule KCH-1521, which decreases adhesion-dependent angiogenesis. KCH-1521, however, does not distinguish between talin1 and talin2 [83]. By contrast, siRNA treatments permit a distinction between talin2 and talin1.…”