Preclinical data on Cyclacel cancer-killing drugs unveiled

Preclinical data demonstrating the ability of Cyclacel Pharmaceuticals cell cycle inhibitors to induce cancer cell death by inhibiting key enzymes has been unveiled at the American Association for Cancer Research (AACR).

The US company's independent investigators presented eight posters at the annual meeting. Five of these preclinical studies evaluated Cyclacel's CYC116 cell cycle inhibitor. The studies provide additional evidence that CYC116 inhibits Aurora kinases and Vascular Endothelial Growth Factor Receptor-2 tyrosine kinase or VEGFR-2 kinase. Aurora kinases are target proteins that are essential for mitosis or the process by which a cell divides. VEGFR-2 kinase is a validated target promoting angiogenesis or new vessel formation in the vicinity of cancer cells.

"The preclinical data presented at AACR support our understanding that CYC116 has both anti-mitotic and anti-angiogenic activity and help direct our development plan for this drug candidate," said Gregory Reyes, senior vice president of research for Cyclacel Pharmaceuticals. "The ability of CYC116 to target both Aurora and VEGFR2 kinases suggests that it may have potential utility in a range of solid tumours and also haematologic malignancies."

CYC116 is a novel, ATP-competitive, pyrimidine drug that is taken by mouth as a capsule. The drug is a selective agent that potently inhibits the enzymes Aurora kinases and VEGFR-2 kinase at comparable levels with a range of 19 to 69 nanomolar.

Median potency of CYC116 in cancer cells is approximately 300 nanomolar. CYC116 has demonstrated a broad spectrum of potent cytotoxic activity against human tumour cell types. Non-clinical efficacy of CYC116 has been demonstrated by the oral route using mouse leukaemia models, in which increased survival was observed, and human solid tumour xenograft models, in which reductions in tumour growth were observed. Cancer cell types that appear to be particularly sensitive to CYC116 are leukaemia, non-small cell lung cancer and pancreatic cancer.

CYC116 works by affecting the cell cycle progression of cancer cells before they enter mitosis or divide to create daughter cancer cells. The mechanism of action of CYC116 affects cancer cells in several ways. CYC116-treated cells display delayed entry into mitosis; defective polymerisation of tubulins, or proteins that make up microtubules which are the target of the taxane drugs; changes in the function of the centrosome, or the cell's microtubule organising centre; and formation of the mitotic spindle, or the highway along which chromosomes and cellular materials are transported from the mother cell to the daughter cells. After cancer cells are treated with CYC116, their spindle checkpoint is inactivated resulting in inhibition of cytokinesis or the process by which a mother cell divides. These defects result in the generation of polyploidy or cells with more than two chromosome sets, multinucleated cells or cells with multiple cores and apoptosis or cancer cell death.

In a mouse model of leukaemia CYC116-treatment induced decreases in tumour cell volume and infiltration of leukaemia cells in the bone marrow and resulted in an increase in life span. No significant effects on body weight or normal bone marrow cells were observed at effective doses of CYC116. Tumour neovascularisation, or creation of new blood vessels around a tumour, was significantly reduced in a dose dependent manner. The data confirm that CYC116 acts as a dual mitotic and angiogenesis inhibitor, a combination of anti-cancer mechanisms, which could have therapeutic benefit in the clinic.

CYC116 is currently being studied in a Phase 1 trial in patients with solid tumours at Roswell Park Cancer Institute in Buffalo, New York, and South Texas Accelerated Research Therapeutics (START) in San Antonio. The study is designed to identify the maximum tolerated dose of CYC116 and evaluate its pharmacokinetic, pharmacodynamic and anti-tumour effects.