Chalcone/1,3,4-Oxadiazole/Benzimidazole 杂化物作为新型抗增殖剂引发凋亡并抑制 EGFR和 BRAFV600E。
Chalcone/1,3,4-Oxadiazole/Benzimidazole hybrids as novel anti-proliferative agents inducing apoptosis and inhibiting EGFR & BRAFV600E.
发表日期：2023 Sep 16
作者：
Fatma Fouad Hagar, Samar H Abbas, Hesham A M Gomaa, Bahaa G M Youssif, Ahmed M Sayed, Dalia Abdelhamid, Mohamed Abdel-Aziz
来源：
PHARMACOLOGY & THERAPEUTICS
摘要：
21世纪最严峻的全球挑战之一是癌症。治疗癌症是一个持续激励研究者创新设计和开发新治疗方法，助力对抗该疾病的目标。我们的目标是基于生物活性杂环结构“苯并咪唑-噁二唑-查尔酮杂交物”开发具有抑制EGFR和诱导凋亡的潜力的新型抗凋亡杂交物。我们预期这些支架通过抑制BRAF、EGFR和Bcl-2并通过激活半胱天冬酶诱导凋亡来显示抗癌活性。新的杂交物7a-x进行了抗增殖、EGFR和BRAFV600E抑制及诱导凋亡活性的评估。对EGFR和BRAFV600E进行了对接研究和动态模拟研究。所有的杂交物在四种测试细胞系上表现出显著的细胞生长抑制活性，IC50范围从0.95μM到12.50μM不等，与多柔比星相当。化合物7k-m表现出最强的EGFR抑制活性，而化合物7e、7g、7k和7l对BRAFV600E具有良好的抑制活性。此外，化合物7k、7l和7m增加了半胱天冬酶3、8、9、细胞色素C和Bax的水平，降低了Bcl-2蛋白的水平。化合物7k-m获得了最佳的结合得分，并显示出几乎相同的结合模式，与EGFR和BRAF活性位点的共结晶埃洛替尼相当。进一步优化后，化合物7k-m可以作为潜在的抗增殖凋亡剂使用。© 2023. Springer Nature Switzerland AG.
One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease.Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases.The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied.All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites.Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization.© 2023. Springer Nature Switzerland AG.