Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 37; pp. 15074 - 15078
• Main Authors: Lecomte, Nicolas, Njardarson, Jon T, Nagorny, Pavel, Yang, Guangli, Downey, Robert, Ouerfelli, Ouathek, Moore, Malcolm A. S, Danishefsky, Samuel J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-09-2011; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cell adhesion & migration; Cell Line, Tumor; Cell lines; Cell Movement; Dosage; Ethers; Ethers - chemical synthesis; Ethers - chemistry; Heterologous transplantation; Humans; Inhibitory concentration 50; Lung cancer; Lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lungs; Macrolides - chemical synthesis; Macrolides - chemistry; Macrolides - therapeutic use; Male; Medical screening; Metastasis; Mice; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - pathology; Physical Sciences; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - therapeutic use; screening; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - pathology; Streptomyces; Tumors; Vehicles; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1015247108

Migrastatin is a biologically active natural product isolated from Streptomyces that has been shown to inhibit tumor cell migration. Upon completion of the first total synthesis of migrastatin, a number of structurally simplified analogs were prepared. Following extensive in vitro screening, a new generation of analogs was identified that demonstrates substantially higher levels of in vitro inhibitory activity, stability and synthetic accessibility when compared to the parent natural product. Herein, we describe two promising ether-derivative analogs, the migrastatin core ether (ME) and the carboxymethyl-ME (CME), which exhibit high efficacy in blocking tumor cell migration and metastasis in lung cancer. These compounds show an in vitro migration inhibition in the micromolar range (IC50: ME 1.5 to 8.2 µM, CME 0.5 to 5 µM). In a human small-cell lung carcinoma (SCLC) primary xenograft model, ME and CME compounds were found to be highly potent in inhibiting overall metastasis even at the lowest dosage used (degree of inhibition: 96.2% and 99.3%, respectively). Together these very encouraging findings suggest that these analogs have promise as potent antimetastatic agents in lung cancer.