17-dimethylaminoethylamino-17-demethoxygeldanamycin

17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) is a semi-synthetic derivative of the natural product geldanamycin, which is an antibiotic originally isolated from the bacterium Streptomyces hygroscopicus. 17-DMAG is primarily studied for its potential use as an anticancer agent due to its ability to inhibit heat shock protein 90 (Hsp90), a molecular chaperone involved in the stabilization and function of many oncoproteins.

Mechanism of Action

17-DMAG functions as an inhibitor of Hsp90, a protein that assists in the proper folding and function of various client proteins, many of which are involved in cell signaling, cell cycle regulation, and apoptosis. By inhibiting Hsp90, 17-DMAG causes the degradation of these client proteins, leading to the disruption of multiple signaling pathways that are crucial for the growth and survival of cancer cells.

Hsp90 inhibitors like 17-DMAG bind to the ATP-binding pocket of Hsp90, preventing its ATPase activity, which is essential for its chaperone function. This results in the ubiquitination and proteasomal degradation of client proteins, ultimately leading to cell death in cancer cells.

Clinical Applications

17-DMAG has been investigated in various clinical trials for its efficacy against different types of cancer, including breast cancer, lung cancer, and leukemia. Its water solubility and oral bioavailability make it a promising candidate compared to other geldanamycin derivatives, which often have poor solubility and require intravenous administration.

Side Effects and Toxicity

As with many anticancer agents, 17-DMAG can cause a range of side effects. Commonly reported adverse effects include gastrointestinal disturbances, hepatotoxicity, and myelosuppression. The development of less toxic and more selective Hsp90 inhibitors remains an area of active research.

Research and Development

Ongoing research is focused on improving the selectivity and reducing the toxicity of 17-DMAG and other Hsp90 inhibitors. Combination therapies with other anticancer agents are also being explored to enhance the therapeutic efficacy of 17-DMAG.

Also see

• Geldanamycin
• Heat shock protein 90
• Anticancer drugs
• Molecular chaperones
• Oncoproteins