Cyclacel & Edinburgh Scientists Solve 3-D Structures of PCNA Complexes: Important Target for New Cancer Treatments

02/18/05 -- Cyclacel Group plc ("Cyclacel"), the cell cycle-based biopharmaceutical company, announced today that Cyclacel researchers and collaborators from the University of Edinburgh have solved the three-dimensional atomic structure of human Proliferating Cell Nuclear Antigen (PCNA), a protein centrally involved in the regulation and coordination of cell cycle progression and DNA replication. The breakthrough is part of Cyclacel's multi-pronged strategy to design and develop drugs that act on the cancer cell cycle through a variety of targets. Insights gained from PCNA architecture are used to design and optimize small molecule inhibitors of the protein, which may be useful in treating patients with cancer. The solution of native and complex structures of human PCNA are featured as the cover story in the February 2005 issue of the Proceedings of the National Academy of Sciences.

PCNA acts as a central control mechanism that enables the proliferation of cancer cells and their spreading out of control. The advance announced today provides the opportunity to develop a new family of drugs that inhibit PCNA and bring the whole complex machinery to a halt. This type of drug could also be used to treat other diseases characterised by uncontrolled cell proliferation, such as autoimmune, inflammatory, kidney diseases and certain infectious diseases.

Cyclacel's CYC102 research program is directed at elucidating potential targets that could be used to design drugs that regulate PCNA function. After earlier advances in understanding the complex biology of these mechanisms, the team succeeded in solving the three-dimensional structure of human PCNA alone and bound to a p21 derived inhibitory molecule using X-ray crystallography, a biophysical technology that determines accurately the position of every atom in the protein.

The Cyclacel and Edinburgh team also studied the molecular assembly of four proteins, including PCNA, which are essential components in the process of cell division. An abnormally high level of PCNA is associated with cancer proliferation and is often used as a marker to help clinicians decide how to treat tumors. Other components, called p21 and cyclins, are tumor suppressor proteins that help block DNA synthesis as cells divide. The findings reveal the detailed molecular architecture of the four protein complex and suggest that p21 acts like double-sided sticky tape to hold PCNA to the other components.

This information is of vital importance to drug designers seeking to make drugs that mimic the body's cancer stopping mechanisms. Guided by the biochemical and structural results the team identified a compact target site on the surface of PCNA that may be exploited in the design of PCNA inhibitor drugs. Such PCNA drugs would act independently or perhaps in combination with other cell cycle drugs under development at Cyclacel such as CDK and Cyclin Groove inhibitors.

Professor Malcolm Walkinshaw, at the University of Edinburgh's Institute of Structural and Molecular Biology, said: "It is the balance between the activities of these proteins that determines whether cells spin out of control or whether they die because cell division stops."

Dr. Robert Jackson, Cyclacel's Chief Scientific Officer, said, "We believe that we now have an excellent 'druggable' target site to give us the opportunity to design drugs that may halt rapidly proliferating cells, such as those found in cancer. The collaboration between Cyclacel and Edinburgh University has enabled a scientific breakthrough by combining the respective strengths of our teams on a target widely thought to be beyond reach for drug design."

About Cyclacel (http://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 eight additional programs at preclinical stages.

Source: Cyclacel