用自然小分子抑制剂调节代谢重编程的结直肠癌治疗新型目标DCTPP1的鉴定
Li Feng1, Xinjia Wang1, Xinrui Guo1
1State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 211198, Nanjing, People's Republic of China.
Angewandte Chemie (International ed. in English)
|August 14, 2024
概括
研究人员发现了一种新的天然化合物,化合物2,该化合物向DCTPP1以对抗结直肠癌 (CRC). 这一发现为CRC治疗提供了有前途的新疗法策略,并突出了DCTPP1作为潜在的生物标志物.
科学领域:
- 自然产品化学 自然产品化学
- 癌症生物学 癌症生物学
- 药物发现 药物发现 药物发现
背景情况:
- 大肠直肠癌 (CRC) 是一种普遍存在的恶性瘤,需要新的治疗点.
- 人类dCTP热酶1 (DCTPP1) 酶,调节核酸池,是CRC的一个尚未探索的目标.
- 对于有效的CRC治疗,急需生物活性小分子.
研究的目的:
- 为了识别具有抗CRC活性的新型化学实体.
- 探索DCTPP1作为结直肠癌的潜在治疗点.
- 研究一种新型天然化合物对CRC的作用机制.
主要方法:
- 从内生物Bipolaris victoriae S27.e中分离并阐明12种前所未有的烯-非化物异构体及其单体的结构.
- 在体外和体内测试以评估分离化合物的抗CRC作用,包括增殖,细胞循环,细胞亡和自.
- 对临床癌症样本的生物信息分析,以将DCTPP1表达与患者存活率相关联.
- 生物化学分析以确定DCTPP1作为化合物2的直接目标,并阐明其作用机制.
主要成果:
- 隔离了12种新的烯-非二烯异构体 (1-12) 和单体 (13-20);化合物1和2具有独特的5/6双循环非二烯结构.
- 化合物2在体外和体内都显著抑制了CRC细胞增殖和通过细胞亡和自诱导的细胞死亡.
- DCTPP1被确定为与CRC存活率差相关的新型标,并且被证明由化合物2直接抑制.
- 化合物2的抗CRC活性通过与DCTPP1结合,抑制其酶功能,并破坏氨基酸代谢重编程来调节.
结论:
- DCTPP1是一种新的潜在生物标志物和结直肠癌的治疗点.
- 化合物2代表了第一个被确定针对DCTPP1.1的天然抗CRC药物候选者.
- 该研究为CRC药物开发提供了一个新的途径,通过准DCTPP1和利用天然产品.
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