Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth in Vivo
Yükleniyor...
Dosyalar
Tarih
2021
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
American Chemical Society
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another ?-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors. © 2021 American Chemical Society.
Açıklama
Anahtar Kelimeler
apoptosis, breast cancer, coumarin, EF2K, elongation factor 2 kinase, molecular modeling, chalcone, coumarin, elongation factor 2 kinase, imidazole derivative, nanoparticle, phosphotransferase inhibitor, protein kinase B, protein p53, animal cell, animal experiment, animal model, apoptosis, Article, blood brain barrier, breast cancer, BT-20 cell line, cancer growth, cancer survival, cardiotoxicity, cell proliferation, colony formation, controlled study, crystal structure, densitometry, drug design, drug synthesis, enzyme active site, enzyme phosphorylation, female, in vitro study, in vivo study, lipophilicity, liposomal delivery, MCF-7 cell line, MDA-MB-231 cell line, MDA-MB-436 cell line, molecular docking, molecular dynamics, molecularly targeted therapy, mouse, nonhuman, pharmacokinetic parameters, priority journal, quantum mechanics, time-dependent inhibition, tumor xenograft, Western blotting
Kaynak
ACS Pharmacology and Translational Science
WoS Q Değeri
N/A
Scopus Q Değeri
Q1
Cilt
4
Sayı
2
