Cyclacel Announces Discovery Of Aurora Kinase Inhibitors

Fort Lauderdale, Florida - 4 December 2004 - Cyclacel Group plc (“Cyclacel”), the UK-based biopharmaceutical company, announced the discovery of a novel series of small molecule, cell cycle drugs inhibiting Aurora kinase in a poster presentation at the American Association for Cancer Research (AACR) Cell Cycle and Cancer: Pathways and Therapies conference taking place here. Cyclacel has advanced a lead compound from this series into preclinical development and is studying several fast-follower candidates.

Aurora kinases are enzymes that help dividing cells share their materials among two daughter cells. In many people with cancer, including breast, colon, leukemia, ovary, pancreas, and stomach tumors, Aurora kinase malfunctions and normal control of cell division is lost resulting in abnormal growth. Small molecule drugs that inhibit Aurora kinase may slow down the growth of cancer cells and lead to their death.

The poster reported that after dosing by mouth a representative Aurora inhibitor compound significantly prolonged survival in a leukemia in vivo model. It also showed anti-tumor activity after oral administration in a Non-Small Cell Lung Cancer in vivo model. Its cellular mode of action against proliferating cells was consistent with Aurora A and B modulation as it inhibited histone H3 phosphorylation, slowed entry into mitosis, blocked cytokinesis and caused polyploidy.

The compounds were discovered within a panel of protein kinase inhibitors through cellular phenotype analysis after Cyclacel scientists observed their effects on the progression of cells through mitosis. The compounds were found to potently inhibit Aurora kinase at low nanomolar concentrations, were highly selective for Aurora kinase over a large number of other kinase enzymes and killed a wide range of tumor cell types. They broadly demonstrated oral bioavailability with one molecule reaching 99% availability by mouth dosing.

Aurora kinases are enzymes that were first discovered in the fruit fly model of human cancer by Prof. David Glover, Chief Scientist of Cyclacel’s Polgen Division in Cambridge, UK. Professor Glover is a world authority on Aurora kinases, Polo kinases and related mechanisms controlling cell division. He studied extensively and described in detail the role played by such enzymes in regulating the late stage of the cell cycle known as mitosis.

Cyclacel scientists under the direction of Professor Glover have identified several hundred genes regulating mitosis and amassed a substantial intellectual property estate on possible drug targets. Cyclacel’s expertise in the mitosis field includes the use of state-of-the-art interference RNA and automated high-throughput cellular phenotype imaging techniques. Application of these techniques and insight into mitotic mechanisms has been employed to synthesize a large number of novel small molecule compounds inhibiting Aurora kinase, Polo-like Kinase 1 (Plk1) and other undisclosed targets in mitosis.

Prof. David Glover, Chief Scientist of Cyclacel’s Polgen Division, said: “Aurora kinases are key regulators of mitosis and are known to be malfunctioning in large numbers of cancer cells. Nine years after the discovery of Aurora it is gratifying that our knowledge of mitosis biology has resulted through Cyclacel’s efforts in specific small molecule Aurora inhibitors. I am excited about the prospects of these compounds as potential anticancer treatments as they advance into preclinical and eventually clinical evaluation assisted by biomarkers.”

About Cyclacel ( www.cyclacel.com )
Cyclacel is a biopharmaceutical company dedicated to the discovery, development and commercialization of novel, mechanism-targeted drugs to treat human cancers and other serious disorders. The company is currently evaluating seliciclib (CYC202), an orally-available cyclin dependent kinase inhibitor, in Phase II clinical trials for the treatment of non-small cell lung cancer and B-cell hematological malignancies. CYC682 is an orally-available, cell cycle modulating nucleoside analog in Phase I clinical trials for the treatment of cancer. Cyclacel also has seven programs in preclinical development.

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