7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo[2,3-d] pyrimidin-4-ylamine inhibits the proliferation and migration of vascular smooth muscle cells by suppressing ERK and Akt pathways

• Published in: European journal of pharmacology 2017-03, Vol.798, p.35-42
• Main Authors: Seo, Hyang-Hee, Kim, Sang Woo, Lee, Chang Youn, Lim, Kyu Hee, Lee, Jiyun, Lim, Soyeon, Lee, Seahyoung, Hwang, Ki-Chul
• Format: Article
• Language: English
• Subjects: 3-d] pyrimidin-4-ylamine; 7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo; Animals; Cell Cycle - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Extracellular Signal-Regulated MAP Kinases - metabolism; Migration; Muscle, Smooth, Vascular - cytology; Proliferation; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; VSMC
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.02.004

Excessive vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury significantly contributes to the development of occlusive vascular disease. Therefore, inhibiting the proliferation and migration of VSMCs is a validated therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. In the present study, we screened chemical compounds for their anti-proliferative effects on VSMCs using multiple approaches, such as MTT assays, wound healing assays, and trans-well migration assays. Our data indicate that 7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo[2,3-d] pyrimidin-4-ylamine, a lymphocyte-specific protein tyrosine kinase (Lck) inhibitor, significantly inhibited both VSMC proliferation and migration. 7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo[2,3-d]pyrimidin-4-ylamine suppresses VSMC proliferation and migration via down-regulating the protein kinase B (Akt) and extracellular signal regulated kinase (ERK) pathways, and it significantly decreased the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and, the phosphorylation of retinoblastoma protein (pRb). Additionally, 7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo[2,3-d] pyrimidin-4-ylamine suppressed the migration of VSMCs from endothelium-removed aortic rings, as well as neointima formation following rat carotid balloon injury. The present study identified 7-cyclopentyl-5-(4-phenoxyphenyl)−7H-pyrrolo[2,3-d]pyrimidin-4-ylamine as a potent VSMC proliferation and migration inhibitor and warrants further studies to elucidate its more detailed molecular mechanisms, such as its primary target, and to further validate its in vivo efficacy as a therapeutic agent for pathologic vascular conditions, such as restenosis and atherosclerosis.