Campbell Paul M, Boufaied Nadia, Fiordalisi James J, Cox Adrienne D, Falardeau Pierre, Der Channing J, Gourdeau Henriette
Lineberger Comprehensive Cancer Center and Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill NC 27599-7295, USA.
J Mol Signal. 2010 Nov 2;5:18. doi: 10.1186/1750-2187-5-18.
TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered using Thallion's proprietary DECIPHER® technology, a genomics and bioinformatics platform that predicts the chemical structures of secondary metabolites based on gene sequences obtained by scanning bacterial genomes. Our recent studies suggest that TLN-4601 inhibits the Ras-ERK MAPK pathway post Ras prenylation and prior to MEK activation. The Ras-ERK MAPK signaling pathway is a well-validated oncogenic cascade based on its central role in regulating the growth and survival of cells from a broad spectrum of human tumors. Furthermore, RAS isoforms are the most frequently mutated oncogenes, occurring in approximately 30% of all human cancers, and KRAS is the most commonly mutated RAS gene, with a greater than 90% incidence of mutation in pancreatic cancer.
To evaluate whether TLN-4601 interferes with K-Ras signaling, we utilized human pancreatic epithelial cells and demonstrate that TLN-4601 treatment resulted in a dose- and time-dependent inhibition of Ras-ERK MAPK signaling. The compound also reduced Ras-GTP levels and induced apoptosis. Finally, treatment of MIA PaCa-2 tumor-bearing mice with TLN-4601 resulted in antitumor activity and decreased tumor Raf-1 protein levels.
These data, together with phase I/II clinical data showing tolerability of TLN-4601, support conducting a clinical trial in advanced pancreatic cancer patients.
TLN - 4601是一种结构新颖的法尼基化二苯并二氮杂䓬酮，它是利用Thallion公司专有的DECIPHER®技术发现的，该技术是一个基因组学和生物信息学平台，可根据通过扫描细菌基因组获得的基因序列预测次生代谢产物的化学结构。我们最近的研究表明，TLN - 4601在Ras异戊二烯化后和MEK激活前抑制Ras - ERK MAPK途径。Ras - ERK MAPK信号通路是一个经过充分验证的致癌级联反应，因为它在调节多种人类肿瘤细胞的生长和存活中起着核心作用。此外，RAS亚型是最常发生突变的致癌基因，在所有人类癌症中约占30%，而KRAS是最常见的突变RAS基因，在胰腺癌中的突变发生率超过90%。
为了评估TLN - 4601是否干扰K - Ras信号传导，我们使用了人胰腺上皮细胞，并证明TLN - 4601处理导致Ras - ERK MAPK信号传导呈剂量和时间依赖性抑制。该化合物还降低了Ras - GTP水平并诱导了细胞凋亡。最后，用TLN - 4601处理携带MIA PaCa - 2肿瘤的小鼠产生了抗肿瘤活性，并降低了肿瘤Raf - 1蛋白水平。
这些数据，连同显示TLN - 4601耐受性的I/II期临床数据，支持在晚期胰腺癌患者中开展临床试验。
