Compounds that Selectively Induce Cancerous Cell Death in the G1 Phase of the Cell Cycle


Malignant melanoma is a cancer that is refractory to current chemotherapeutic treatments. Through the synthesis of a combinatorial library of potential proapoptotic agents, a novel class of small molecules (triphenylmethylamides, TPMAs) have been identified that are effective agents in killing melanoma cells, as well as other cancer cells. 

The majority of anticancer drugs operate through induction of cell cycle arrest and cell death in either the DNA synthesis (S) or mitosis (M) phase of the cell cycle. In contrast, these TPMAs, act in the G1 phase of the cell cycle. Many of the TPMAs are quite potent inducers of apoptotic death in melanoma cell lines (IC50 of 0.5 ?M), and importantly, some TPMAs are comparatively nontoxic to normal cells isolated from the bone marrow of healthy donors.

Furthermore, the TPMAs dramatically reduce the level of active nuclear factor -B (NFB) in the cell; NFB is known to be constitutively active in melanoma, and this activity is critical for the proliferation of melanoma cells and their evasion of apoptosis. With regard to status of development, multiple generations of compounds have been tested and have shown efficacy with primary melanocytes, while these same compounds have shown to be largely non-toxic in initial rodent studies assessing changes in body weight and death.

In addition, the National Cancer Institute's 60-cell line screen has demonstrated activity of the compounds against a broad range of cancer types.