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A class of small molecules called triphenylmethylamides (TPMAs) has been found to induce apoptosis (cell death) in melanoma cells (J. Am. Chem. Soc. 2005, 127, 8686). The findings could point the way toward potential therapies for malignant melanoma, a particularly deadly form of skin cancer.
Currently, a diagnosis of late-stage melanoma is practically a death sentence. The average survival time for patients with such a diagnosis is only six months.
Paul J. Hergenrother, an assistant professor of chemistry at the University of Illinois, Urbana-Champaign, decided to focus on melanoma after conversations with physicians. "I was really interested in the most untreatable forms of cancer," he says. "As I started reading up on [melanoma], I found that indeed there's only one clinically approved compound, and it has only a 2% efficacy in complete remission. There's really no good treatment."
With their discovery of TPMAs, Hergenrother and his coworkers hope to change the outlook for melanoma treatment.
Unlike most cancer drugs, TPMAs cause cell death during a portion of the cell cycle called the G1 phase. Most other cancer drugs target either DNA synthesis or cell division. Such drugs probably are ineffective against melanoma because the same characteristics that help protect melanocytes (pigment cells) against DNA damage also confer resistance against drugs that target DNA synthesis or cell division.
One of the challenges is to find compounds that kill melanoma cells but do minimal damage to other dividing cells, such as bone marrow cells. In the first set of 100 compounds they looked at, the Illinois researchers found two compounds that kill melanoma cells but also kill bone marrow cells. In a second round of synthesis and screening, they found two compounds, denoted 4AN and 4BI, that are effective against melanoma yet are significantly less toxic to normal cells.
Hergenrother's group is currently searching for the target of TPMAs. A key clue is that they cause a reduction of active nuclear factor kappa-B, a protein known to be active in melanoma and also known to activate a number of antiapoptotic factors.
"We've made many derivatives of the most active compounds reported in this paper and are using them to fish out the target," Hergenrother says. "We can use this compound to try to define totally new targets for the treatment of an intractable problem in cancer."
In addition to being tools for understanding the biology of melanoma, the new compounds could eventually become the starting point for drugs. Studies are currently under way with collaborators to determine whether the compounds are also effective against melanoma in mice.
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