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Cyclacel solve 3-D structures of PCNA complexes

21-Feb-2005

Cyclacel researchers and collaborators have solved the 3-D atomic structure of human Proliferating Cell Nuclear Antigen (PCNA), a protein involved in cancer. The discovery should prove crucial in designing and developing drugs that act on the cancer cell cycle through a variety of targets.

The need for new and effective therapies for treating cancer has become paramount especially as cancer is currently the second leading cause of death in the Western World. Solid tumours in particular represent a major health issue with an incidence of over 2 million people.

Survival rates tend to be poor in many cancers and demographic changes indicate that new cases of cancer are on the rise. The sheer variability and capability of cancers to build immunity towards current treatments are the main areas of frustration for pharmaceutical companies.

The PCNA acts as a central control mechanism that enables the proliferation of cancer cells and its spreading out of control. The breakthrough is part of Cyclacel's multi-pronged strategy to develop a new family of drugs that inhibit PCNA and bring cancerous growth to a halt.

This information obtained from the insights into PCNA's structure is important 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.

Increased understanding of the molecular and genetic mechanism causing cancer have raised possibilities that mechanism-targeted drugs may complement existing chemotherapies with the objective of increasing effectiveness and decreasing toxic side effects of modern cancer therapeutics.

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 , a cell cycle-based biopharmaceutical company, has initiated a research program involving its nucleoside analog CYC102, which 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.

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 tumours. p21 and cyclins, are tumour 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.

Tumour suppressor genes, such as p53 and p21, stop cancer cells at cell cycle checkpoints and cause them to commit suicide. The goal of cancer treatment with cell cycle inhibitors is to emulate tumour suppressor gene behaviour and cause cancer cells to die.

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."

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