migrastatin and Neoplasm-Metastasis

Tumor metastasis is a complex process in which cells detach from the primary tumor and colonize a distant organ. Metastasis is also the main process responsible for cancer-related death. Despite the enormous efforts made to unravel the metastatic process, there is no effective therapy, and patients with metastatic tumors have poor prognosis. In this regard, there is an urgent need for new therapeutic tools for the treatment of this disease. Small molecules with the capacity to reduce cell migration could be used to treat metastasis. Migrastatin-core analogs are naturally inspired macrocycles that inhibit pathological cell migration and are able to reduce metastasis in animal models. Migrastatin analogs can be synthesized from a common advanced intermediate. Herein we present a review of the synthetic approaches that can be used to prepare this key intermediate, together with a review of the biological activity of migrastatin-core analogs and current hypotheses concerning their mechanism of action.

Topics: Animals; Antineoplastic Agents; Biological Products; Cell Line, Tumor; Cell Movement; Drug Evaluation, Preclinical; Humans; Macrolides; Neoplasm Metastasis; Neoplasms; Piperidones

Migrastatin, a macrolide natural product, and its structurally related analogs are potent inhibitors of cancer cell metastasis, invasion and migration. In the present work, a specialized fragment-based method was employed to develop QSAR models for a series of migrastatin and isomigrastatin analogs. Significant correlation coefficients were obtained (best model, q2 = 0.76 and r2 = 0.91) indicating that the QSAR models possess high internal consistency. The best model was then used to predict the potency of an external test set, and the predicted values were in good agreement with the experimental results (R2 pred = 0.85). The final model and the corresponding contribution maps, combined with molecular modeling studies, provided important insights into the key structural features for the anticancer activity of this family of synthetic compounds based on natural products.

Topics: Cell Movement; Databases, Factual; Macrolides; Models, Molecular; Molecular Conformation; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidones; Quantitative Structure-Activity Relationship; Stereoisomerism

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 (IC(50): 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.

Topics: Animals; Cell Line, Tumor; Cell Movement; Ethers; Humans; Lung Neoplasms; Macrolides; Male; Mice; Neoplasm Metastasis; Piperidones; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays

A significantly simpler analog of the natural product migrastatin, termed migrastatin ether (ME), has been prepared and evaluated. Both in vivo and in vitro studies indicate that ME exhibits a concentration-dependent inhibitory effect on migration of breast cancer cells.

Topics: Animals; Antineoplastic Agents; Biological Products; Breast Neoplasms; Cell Movement; Drug Screening Assays, Antitumor; Ethers; Female; Humans; Macrolides; Mice; Molecular Conformation; Neoplasm Metastasis; Piperidones; Stereoisomerism

Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

Topics: Actins; Animals; Antineoplastic Agents; Binding Sites; Breast Neoplasms; Carrier Proteins; Cell Line, Tumor; Cell Movement; Crystallography, X-Ray; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Macrolides; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Microfilament Proteins; Models, Molecular; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidones; Protein Conformation

Tumor metastasis is the most common cause of death in cancer patients. Here, we show that two, fully synthetic migrastatin analogues, core macroketone and core macrolactam, are potent inhibitors of metastasis in a murine breast tumor model. Administration of these readily accessible compounds nearly completely inhibits lung metastasis of highly metastatic mammary carcinoma cells. Treatment of tumor cells with core macroketone and core macrolactam blocks Rac activation, lamellipodia formation, and cell migration, suggesting that these chemical compounds interfere with the invasion step of the metastatic process. These compounds also inhibit the migration of human metastatic breast cancer cells, prostate cancer cells, and colon cancer cells but not normal mammary-gland epithelial cells, fibroblasts, and leukocytes. These data demonstrate that the macroketone and macrolactam core structures are specific small-molecule inhibitors of tumor metastasis. These compounds or their analogues could potentially be used in cancer-therapy strategies.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Humans; Lactones; Lung Neoplasms; Macrolides; Mice; Neoplasm Metastasis; Piperidones; rac GTP-Binding Proteins