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在非小细胞肺癌细胞中鉴定一种靶向KRAS的新型强效抑制剂

Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells.

作者信息

Xie Chun, Li Ying, Li Lan-Lan, Fan Xing-Xing, Wang Yu-Wei, Wei Chun-Li, Liu Liang, Leung Elaine Lai-Han, Yao Xiao-Jun

机构信息

State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.

State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.

出版信息

Front Pharmacol. 2017 Nov 14;8:823. doi: 10.3389/fphar.2017.00823. eCollection 2017.

DOI:10.3389/fphar.2017.00823
PMID:29184501
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5694459/
Abstract

KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogenic driver with mutations in 30% of non-small cell lung cancer (NSCLC). However, there is no effective clinical drug even though it has been identified as an oncogene for 30 years. In this study, we identified a small molecule inhibitor compound 0375-0604 targeting KRAS by using molecular docking based virtual screening approach. Compound 0375-0604 had a good binding affinity to KRAS and exhibited cytotoxicity in oncogenic KRAS expressing NSCLC cell lines. Further mechanism study showed that compound 0375-0604 can block the formation of the complex of guanosine triphosphate (GTP) and KRAS . In addition, compound 0375-0604 inhibited KRAS downstream signaling pathway RAF/MEK/ERK and RAF/PI3K/AKT. Finally, we also found that this compound can inhibit the cell growth through G2/M cell cycle arrest and induce apoptosis on the NSCLC cell lines harboring KRAS mutation. Therefore, compound 0375-0604 may be considered as a potential KRAS inhibitor for treatment of NSCLC carrying KRAS oncogene.

摘要

KRAS（v-Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物）是一种致癌驱动因子，在30%的非小细胞肺癌（NSCLC）中发生突变。然而，尽管它被确定为致癌基因已有30年，但目前尚无有效的临床药物。在本研究中，我们使用基于分子对接的虚拟筛选方法，鉴定出一种靶向KRAS的小分子抑制剂化合物0375-0604。化合物0375-0604对KRAS具有良好的结合亲和力，并在表达致癌KRAS的NSCLC细胞系中表现出细胞毒性。进一步的机制研究表明，化合物0375-0604可以阻断三磷酸鸟苷（GTP）与KRAS复合物的形成。此外，化合物0375-0604抑制KRAS下游信号通路RAF/MEK/ERK和RAF/PI3K/AKT。最后，我们还发现该化合物可通过G2/M期细胞周期阻滞抑制细胞生长，并诱导携带KRAS突变的NSCLC细胞系凋亡。因此，化合物0375-0604可被视为治疗携带KRAS致癌基因的NSCLC的潜在KRAS抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/7a84f2361b76/fphar-08-00823-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/8b12a4c5ee06/fphar-08-00823-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/89bca79d3af5/fphar-08-00823-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/0bf144b09c59/fphar-08-00823-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/3d1014aa7fa4/fphar-08-00823-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/f3b297248647/fphar-08-00823-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/7a84f2361b76/fphar-08-00823-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/8b12a4c5ee06/fphar-08-00823-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/89bca79d3af5/fphar-08-00823-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/0bf144b09c59/fphar-08-00823-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/3d1014aa7fa4/fphar-08-00823-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/f3b297248647/fphar-08-00823-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c593/5694459/7a84f2361b76/fphar-08-00823-g006.jpg

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