Investigation of the Effects of Benzimidazole Derivatives on the mTOR Pathway in Breast Cancer

Yıl 2025, Cilt: 18 Sayı: 2, 361 - 371, 31.08.2025

Ronak Haj Ersan , Omer Faruk Col

https://doi.org/10.18185/erzifbed.1655269

Öz

The mammalian target of rapamycin (mTOR) pathway plays a critical role in cancer progression, making it a key target for therapeutic intervention. Dysregulation of mTOR signaling is frequently observed in malignancies, highlighting the need for potent and selective inhibitors. In this study, a series of benzimidazole derivatives were designed and evaluated for their potential as mTOR inhibitors. Cytotoxicity assessments using MTT assays demonstrated that compounds 10 and 15 exhibited significant anti-proliferative effects against breast cancer cell lines, with IC₅₀ values of 6.63 µM and 5.28 µM, respectively. Further biochemical studies revealed that the most active compounds effectively suppressed mTOR phosphorylation at Ser2448 in MCF-7 cells, as confirmed by colorimetric enzymatic activity assays. These results suggest that compound 15, in particular, represents a promising lead for the development of novel mTOR-targeted therapies. This study provides valuable insights into the structure-based design of mTOR inhibitors, offering a foundation for future advancements in targeted cancer treatment.

Anahtar Kelimeler

Benzimidazole , mTOR inhibitory activity , structure-activity relationship

Benzimidazol Türevlerinin mTOR Yolağı Üzerindeki Etkilerinin Meme Kanserinde Araştırılması

Öz

Rapamisin memeli hedefi (mTOR) sinyal yolu, kanser ilerlemesinde kritik bir rol oynayarak terapötik müdahaleler için önemli bir hedef haline gelmiştir. mTOR sinyal iletiminin düzensizliği, malignitelerde sıkça gözlemlenmekte olup, güçlü ve seçici inhibitörlere olan ihtiyacı vurgulamaktadır. Bu çalışmada, bir dizi benzimidazol türevi tasarlanmış ve potansiyel mTOR inhibitörleri olarak değerlendirilmiştir. MTT analizleri ile yapılan sitotoksisite değerlendirmeleri, 10 ve 15 numaralı bileşiklerin meme kanseri hücre hatlarına karşı belirgin anti-proliferatif etki gösterdiğini ortaya koymuş ve IC₅₀ değerleri sırasıyla 6,63 µM ve 5,28 µM olarak belirlenmiştir. Biyokimyasal incelemeler, en aktif bileşiklerin MCF-7 hücrelerinde Ser2448 bölgesinde mTOR fosforilasyonunu etkili bir şekilde baskıladığını ve bu durumun kolorimetrik enzim aktivite testleriyle doğrulandığını göstermiştir. Elde edilen bulgular, özellikle 15 numaralı bileşiğin yeni mTOR hedefli tedavilerin geliştirilmesi için umut verici bir öncü olabileceğini ortaya koymaktadır. Bu çalışma, mTOR inhibitörlerinin yapı bazlı tasarımına dair değerli bilgiler sunarak hedefe yönelik kanser tedavilerinin gelecekteki gelişmelere katkı sağlayacaktır.

Anahtar Kelimeler

Benzimidazol , mTOR inhibitör aktivite , yapı-aktivite ilişkisi

Kaynakça

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