Kanser tedavisinde kullanılabilecek, moleküler modelleme tabanlı yeni protein kinaz inhibitörlerinin tasarımı, sentezi ve etkinliklerinin incelenmesi
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Tarih
2019
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Çanakkale Onsekiz Mart Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Meme kanserlerinin %15-20'sini içeren TNMK, triple negatif (TN) tümörlerin yanısıra östrojen reseptör ?–pozitif (Er+) ve HER2+ tümörlerinde sınıflandırılan çok türlü bir hastalık olan agresif tip meme kanserinin bir alt türüdür. EF2-Kinaz (EF2K), üçlü negatif ve pankreas kanserlerini içeren agresif katı tümörlerin tedavisi için ortaya çıkan moleküler bir hedeftir. eEF-2K etkinliğinin artması ile meme, pankreas, yumurtalık, akciğer vb. kanser hücrelerinde tümör büyümesi, yayılması (invazyon ve metastaz), kemoterapiye direnç gelişimi artar. Son zamanlarda eEF-2K hedefli etkili inhibitörlerin geliştirilmesine olan ilgi oldukça artmıştır. Bu çalışmada, eEF2K inhibitörü olabilecek farklı tip çekirdek yapılar (kumarin, kinazolin, oksoindol, fenil üre, 1,2,4-oksadiazol, üçüncül amin, neo-tanshinlakton) ve fonksiyonel gruplar içeren birçok bileşik tasarlanmıştır ve içlerinden en etkin olabilecek 50 adet bileşiğin sentezi gerçekleştirilmiştir. Moleküler kenetlenme, ADMET ve 3D QSAR (PHASE) analizleri gibi hesaplamalı kimya teknikleri kullanılmıştır. Sentezlenen bileşiklerin in vitro western blot ve klonojenik analiz çalışmaları ile ve in vivo ortotopik xenograft mouse klinik öncesi çalışmaları gerçekleştirilmiştir. Düşük (0.1-1 µM) dozlarda etkili olan kumarin kalkon bileşikleri ile boronat ester işlevsel grupları içeren bileşikler, potansiyel inhibitörler olarak bulunmuştur. TNMK ve pankreas hücrelerinde apoptosise neden olduğu belirlenmiştir. Anahtar Kelimeler: eEF2K, TNMK, Pankreas Kanseri, Boronik Bileşikler, In siliko
TNBC, which contains 15-20% of breast cancers, is a subspecies of aggressive type of breast cancer which is a heterogeneous disease classified as triple negative (TN) tumors as well as estrogen receptor ? – positive (Er +) and HER2 + tumors. EF2-Kinase (EF2K) is a molecular target for treatment of highly aggressive solid cancers including triple negative and pancreatic cancers. Increasing of eEF-2K activity causes to tumor growth, proliferation (invasion and metastasis), resistance to chemotherapy in cancer cells such as breast, pancreas, ovary, lung etc. Therefore, recently the interest in the development of effective inhibitors targeting eEF2K significantly increased. In this study, we designed several compounds which contain different type core structures (coumarin, quinazoline, oxindole, phenyl urea, 1,2,4-oxadiazole, tertiary amine, neo-tanshinlactone) and functional groups and synthesized the most active 50 compounds among them. Computational techniques such as Molecular Docking, ADMET and 3D QSAR PHASE analysis were also used. Synthesized compounds were examined for their in vitro activity with Western blot analysis and clonogenic assay and in vivo activity with orthotopic xenograft tumor model. Coumarin chalcone and boronate ester compounds were found potential inhibitors that are highly effective at submicromolar concentration doses as low as 0.1-1 µM and observed to cause apoptosis in TNBC and pancreatic cells. Keywords: eEF2K, TNBC, Pancreatic Cancer, Boronic Compounds, In Silico
TNBC, which contains 15-20% of breast cancers, is a subspecies of aggressive type of breast cancer which is a heterogeneous disease classified as triple negative (TN) tumors as well as estrogen receptor ? – positive (Er +) and HER2 + tumors. EF2-Kinase (EF2K) is a molecular target for treatment of highly aggressive solid cancers including triple negative and pancreatic cancers. Increasing of eEF-2K activity causes to tumor growth, proliferation (invasion and metastasis), resistance to chemotherapy in cancer cells such as breast, pancreas, ovary, lung etc. Therefore, recently the interest in the development of effective inhibitors targeting eEF2K significantly increased. In this study, we designed several compounds which contain different type core structures (coumarin, quinazoline, oxindole, phenyl urea, 1,2,4-oxadiazole, tertiary amine, neo-tanshinlactone) and functional groups and synthesized the most active 50 compounds among them. Computational techniques such as Molecular Docking, ADMET and 3D QSAR PHASE analysis were also used. Synthesized compounds were examined for their in vitro activity with Western blot analysis and clonogenic assay and in vivo activity with orthotopic xenograft tumor model. Coumarin chalcone and boronate ester compounds were found potential inhibitors that are highly effective at submicromolar concentration doses as low as 0.1-1 µM and observed to cause apoptosis in TNBC and pancreatic cells. Keywords: eEF2K, TNBC, Pancreatic Cancer, Boronic Compounds, In Silico
Açıklama
Fen Bilimleri Enstitüsü, Kimya Ana Bilim Dalı
Anahtar Kelimeler
Biyoteknoloji, Biotechnology, Eczacılık ve Farmakoloji
