Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS(G12C).
Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS(G12C).
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合成碳氢钉合肽在表达 KRAS(G12C) 的 H358 癌细胞中诱导细胞凋亡的活性
DOI：
10.1016/j.apsb.2021.06.013
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Li C;Zhao N;An L;Dai Z;Chen X;Yang F;You Q;Di B;Hu C;Xu L
肺癌是全球癌症死亡的主要原因，严重威胁人类的生命和健康。非小细胞肺癌（NSCLC）是最常见的恶性肿瘤，占所有肺癌亚型的80%。除了其他突变（例如，KRASG 12 V/D），KRASG 12 C基因突变是NSCLC的重要驱动力，在所有NSCLC患者中的患病率约为14%。然而，目前只有少数针对KRASG 12 C突变的治疗药物。在这里，我们合成了烃钉合肽3，它更短，更稳定，具有适度的KRASG 12 C结合亲和力，并且基于α-螺旋肽模拟物SAH-SOS 1A具有相同的抗肿瘤作用。从基因组学和蛋白质组学的角度证实了钉合肽3通过阻断KRAS介导的RAF/MEK/ERK信号通路，有效诱导KRAS突变肺癌细胞G2/M期阻滞和凋亡，抑制细胞生长。肽3还表现出强的抗胰蛋白酶和抗胰凝乳蛋白酶能力，以及良好的血浆稳定性和人肝微粒体代谢稳定性。总体而言，肽3保留了SAH-SOS 1A的等效抗肿瘤活性，但具有改善的稳定性和亲和力，优于SAH-SOS 1A，上级。我们的工作提供了一种用于癌症治疗的KRASG 12 C肽抑制剂的结构优化方法。钉合肽3通过阻断KRAS介导的信号通路，诱导细胞G2/M期阻滞和凋亡，抑制H358细胞生长，对蛋白水解有较强的抵抗力，稳定性好。
Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health. Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying 80% of all lung cancer subtypes. Except for other mutations (e.g., KRASG12V/D) that are also vital for the occurrence, KRASG12C gene mutation is a significant driving force of NSCLC, with a prevalence of approximately 14% of all NSCLC patients. However, there are only a few therapeutic drugs targeting KRASG12C mutations currently. Here, we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRASG12C binding affinity and the same anti-tumor effect based on the α-helical peptide mimic SAH-SOS1A. The stapled peptide 3 effectively induced G2/M arrest and apoptosis, inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRAS-mediated RAF/MEK/ERK signaling, which was verified from the perspective of genomics and proteomics. Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities, as well as good plasma stability and human liver microsomal metabolic stability. Overall, peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1A but with improved stability and affinity, superior to SAH-SOS1A. Our work offers a structural optimization approach of KRASG12C peptide inhibitors for cancer therapy. The stapled peptide 3 could induce G2/M arrest and apoptosis to inhibit H358 cells growth by disrupting KRAS-mediated signaling pathway, and showed strong resistance to proteolysis and had good stability.
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DOI：
10.1073/pnas.1812963116
发表时间：
2019-02-12
影响因子：
11.1
作者：
Hillig, Roman C.;Sautier, Brice;Bader, Benjamin
通讯作者：
Bader, Benjamin
影响因子：
7.3
作者：
Chen, Hao;Smaill, Jeff B.;Lu, Xiaoyun
通讯作者：
Lu, Xiaoyun
DOI：
10.1073/pnas.93.4.1577
发表时间：
1996-02-20
影响因子：
11.1
作者：
Clark, GJ;Drugan, JK;Campbell, S
通讯作者：
Campbell, S
评估MEK抑制在KRAS（G12C）驱动的肺癌模型中的治疗功效。
DOI：
10.1158/1078-0432.ccr-17-3438
发表时间：
2018-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li S;Liu S;Deng J;Akbay EA;Hai J;Ambrogio C;Zhang L;Zhou F;Jenkins RW;Adeegbe DO;Gao P;Wang X;Paweletz CP;Herter-Sprie GS;Chen T;Gutiérrez-Quiceno L;Zhang Y;Merlino AA;Quinn MM;Zeng Y;Yu X;Liu Y;Fan L;Aguirre AJ;Barbie DA;Yi X;Wong KK
通讯作者：
Wong KK
影响因子：
64.5
作者：
Janes, Matthew R.;Zhang, Jingchuan;Liu, Yi
通讯作者：
Liu, Yi