Cyclacel Announces Discovery of Aurora Kinase Inhibitors
FORT LAUDERDALE, Fla.--(BUSINESS WIRE)--Dec. 4, 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 has seven additional programs at preclinical and research stages.
Notes for Editors:
American Association for Cancer Research Conference, Cell Cycle and Cancer: Pathways and Therapies. Dec 1-5 2004, Fort Lauderdale, Florida.
Abstract 1471: Discovery, optimisation and pharmacological evaluation of 2-anilino-4-heteroaryl-pyrimidines as potent orally bioavailable Aurora kinase inhibitors.
Professor David Glover, FRSE, Chief Scientist, Polgen Division. Professor Glover joined Cyclacel in November 1999. He is Arthur Balfour Professor of Genetics and Chairman in the Department of Genetics at the University of Cambridge. He is also Director of Cancer Research UK Cell Cycle Genetics Research Group. He was previously Professor of Molecular Genetics at the University of Dundee and Professor and Head of Biochemistry at Imperial College, London. Professor Glover discovered and named the Polo and Aurora mitotic protein kinases and coordinated the former European Drosophila Genome Project, the European academic consortium contributing to sequencing the fruit fly genome. He is a member of the European Molecular Biology Organisation and has authored over 200 publications and patents.
Cancer and Aurora Kinase Inhibitors
Cancer is the second leading cause of death in the Western World. Solid tumors represent a major public health issue with an incidence of over 2 million people. Breast, colorectal, lung, prostate cancer and leukemia are the most common. Survival rates tend to be poor in many cancers and demographic changes and graying populations suggest that new cases of cancer are on the rise. Increased understanding of the molecular and genetic mechanism causing cancer have raised expectations that mechanism-targeted drugs may complement existing chemotherapies with the objective of increasing effectiveness and decreasing toxic side effects of modern cancer therapeutics.
Mitosis is the last stage of the cell division cycle during which copied genetic material from the nucleus of a parent cell is endowed into two daughter cells. The accuracy of the mitotic process determines the survival of the daughter cells. To ensure the integrity of this process the body uses mechanisms such as the Aurora kinases to check cells for errors that may cause genomic instability and result in cancer.
Aurora kinases are enzymes discovered by Professor David Glover(1) that help cells regulate how they share their materials among two daughter cells as they divide during mitosis. This mechanism helps regulate how cells grow and multiply. In many people with cancer, including leukemia, colon and breast 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.
Literature references suggest that Aurora kinase inhibitor drugs do not induce cell cycle arrest in cancer cells as is the case with classical anti-mitotic agents such as the taxanes. Instead Aurora kinase inhibitors delay entry into mitosis and drive cells into an aberrant mitosis condition called mitotic catastrophe. In effect these drugs disrupt the genome and derail the orderly division of cancer cells in the next cell cycle causing their death. The distinct mechanism of Aurora kinase inhibitors suggests the possibility of synergy in combination with anti-mitotic drugs.
* © 2004 - Cyclacel Group plc. Cyclacel®, Fluorescience®, Penetratin® and Polgen® are registered trademarks.
* (1)Glover D.M., Leibowitz M.H., McLean D.A., Parry H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 1995 Apr 7:81(1):95-105. |
