17-AAG, also known as Tanespimycin, is an experimental compound investigated for cancer treatment. It is a derivative of a natural antibiotic called geldanamycin, which was first identified as a heat shock protein 90 (Hsp90) inhibitor. While geldanamycin itself proved too toxic for clinical use, its derivative 17-AAG showed promise with reduced toxicity and entered clinical trials for various human cancers. The exploration of 17-AAG marked a step in developing drugs that target a protein cancer cells heavily depend on for survival and growth.
The Role of Heat Shock Protein 90 in Cancer
Within healthy cells, proteins known as “chaperones” help other newly made proteins fold into their correct three-dimensional shapes. One of these chaperones, Heat Shock Protein 90 (Hsp90), is important for stabilizing a select group of proteins involved in signal transduction and cell cycle regulation. These “client proteins” are necessary for a cell’s response to external signals and internal stress. Hsp90 ensures these proteins remain functional and are not prematurely degraded.
Cancer cells exist in a state of high physiological stress, characterized by rapid proliferation and genetic mutations. This environment leads to the production of numerous mutated and unstable proteins necessary for the cancer’s growth and survival. Many of these cancer-promoting proteins, such as HER2, Raf-1, and Akt, are client proteins of Hsp90. They are structurally abnormal and would be quickly destroyed without constant support from Hsp90.
This intense reliance makes Hsp90 a compelling target for therapy. Because cancer cells are exceptionally dependent on the protein to maintain the oncoproteins driving their behavior, inhibiting Hsp90 can selectively undermine a cancer cell with a lesser effect on normal cells. This dependency is why inhibitors like 17-AAG were pursued as a targeted treatment.
Mechanism of Action
17-AAG works by directly interfering with the function of the Hsp90 protein. The drug specifically binds to a region on Hsp90 known as the N-terminal ATP-binding pocket. This pocket is where Hsp90 binds to adenosine triphosphate (ATP), the molecule that provides energy for its chaperone activities. By occupying this site, 17-AAG competitively blocks ATP from binding, effectively shutting down the protein’s function.
This binding event triggers a conformational change in the Hsp90 protein, rendering it incapable of supporting its client proteins. Without the stabilizing influence of Hsp90, these client proteins—many of which are drivers of cancer growth—become destabilized. The cell then recognizes these unfolded and non-functional proteins as damaged.
Once destabilized, the client proteins are tagged with a molecule called ubiquitin. This tagging marks them for destruction by the proteasome, the cell’s machinery for degrading unwanted proteins. The targeted degradation of multiple cancer-promoting proteins simultaneously overwhelms the cancer cell, leading to a halt in proliferation and, ultimately, programmed cell death, or apoptosis.
Clinical Development and Limitations
After promising preclinical results, 17-AAG advanced into human clinical trials, generating interest in the oncology community. It was evaluated in Phase I and Phase II trials for cancers including melanoma, breast cancer, and multiple myeloma. These studies showed that 17-AAG could be safely administered and achieve active concentrations in patients, with some signs of clinical activity.
Despite this initial promise, the clinical development of 17-AAG was halted due to major challenges. A primary obstacle was its poor water solubility, which created difficulties in formulating a stable version for intravenous administration. Early formulations required large volumes of organic solvents, which could contribute to toxicity.
Another issue that emerged was dose-limiting hepatotoxicity, or liver damage. This side effect restricted the amount of the drug that could be safely given, making it difficult to achieve a lasting anti-tumor effect. The combination of formulation challenges and liver toxicity prevented 17-AAG from becoming a successful cancer therapy.
The Emergence of Second-Generation Inhibitors
Although 17-AAG did not achieve clinical success, its development provided a “proof of concept” that targeting Hsp90 was a viable strategy. The specific failures of 17-AAG, such as poor solubility and liver toxicity, provided a clear roadmap for improvement in subsequent drug discovery efforts.
This led to the development of second-generation Hsp90 inhibitors, created to overcome the limitations of 17-AAG. One such derivative was 17-DMAG (alvespimycin), which offered higher water solubility and better bioavailability. Another example, retaspimycin (IPI-504), was a highly water-soluble version of 17-AAG designed to convert to the active drug within the body.
These newer agents, along with fully synthetic compounds like ganetespib, were engineered for more favorable pharmacological properties and reduced toxicity. While some of these successors also faced challenges in clinical trials, the work built upon the foundation laid by 17-AAG. The story of 17-AAG illustrates how an initial compound’s shortcomings can pave the way for more refined therapies.