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. The average survival time for patients is 6 months. This coupled with the alarming rise in incidence of melanoma (46,170 cases of in situ melanoma are expected to be newly diagnosed in 2005) warrants research into novel means to treat melanoma. 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 (NF?B) in the cell; NF?B 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. Additional detailed information about this technology can be found in the recently published article: Synthesis and Identification of Small Molecules that Potently Induce Apoptosis in Melanoma Cells through G1 Cell Cycle Arrest (JACS 2005, 127, 8686-8696)

Applications

  • Chemotherapeutic treatment of Melanoma Chemotherapeutic treatment against other cancers, such as breast, colon, non-small cell lung carcinoma (NSCLC), etc.
  • As a research reagent that arrests cells in G1.¬†

Benefits

  • Potent death inducers in melanoma cell lines with potencies in the 0.5 - 1.0 M range
  • Markedly less (8-12-fold) toxicity to the non-cancerous human bone marrow cells
  • National Cancer Institute's 60-cell line screen demonstrated the compounds are quite active against a broad spectrum of cancers and confirmed the IC50 value of 600 nM against the UACC-62 melanoma cell line Initial animal testing suggests that mice can tolerate concentrations as high as 200 mg/kg Efficacy and water solubility are being increased as additional chemical modifications are made with later generation compounds¬†