May 27, 2005
A hallmark of cancer cells is that their internal wiring has been modified to prompt their abnormal growth. This has led some cancer researchers to suspect the most effective chemotherapeutic drugs might be those that target proteins influencing not one but multiple wires within the tumor cells. One such protein is called heat shock protein 90, or Hsp90, a so-called “molecular chaperone” that helps to fold various cancer-causing proteins into their proper three-dimensional configurations. Studies indicate Hsp90 is present at two to 10-fold higher levels in tumor cells than in normal cells. They also show Hsp90 is found in tumor cells in a distinct molecular form that has a 100-fold higher affinity for ansamycin antibiotics, natural compounds that microbes produce to protect themselves from disease causing substances, than the Hsp90 present in normal cells. The challenge has been to synthesize an ansamycin-derived compound that kills tumor cells but which also is relatively straightforward to formulate. In the May 15 issue of the journal Clinical Cancer Research, NIDCR grantees report promising early results with such a compound called EC5. It is a novel dimerized, or two headed, form of geldanamycin, an ansamycin-derived compound. As reported in their paper, EC5 proved more effective at inhibiting the growth of eight head and neck cancer cell lines than the related compound 17-AAG, which is already in clinical trials. In addition, EC5 shrunk a type of head and neck tumor in mice that 17-AAG proved ineffective against. As the scientists noted, “EC5 is one of the most active of a series of divalent Hsp90 inhibitors and the length and flexibility of the linker between the two geldanamycin pharmacores is critical to potency of EC5 and other highly active dimers.”