The US patent (6,531,479) relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia and psoriasis.
Cell cycle inhibitors are an area of growing interest to the pharmaceutical industry because of the importance of Cyclin Dependent Kinases (CDK) and cyclin drug targets in cancer biology.
Cyclin Dependent Kinase (CDK) inhibitors are a novel class of drugs that act on the same CDK enzyme targets as the body's own cancer stopping genes. 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 CDK inhibitors is to emulate tumour suppressor gene behaviour and cause cancer cells to die.
One group of these novel compounds works by inhibiting CDK, focusing on drug targets that control cancer cell division. Further groups of compounds within the series work by inhibiting alternative CDK target profiles and other cell cycle kinases. Cell cycle inhibitors may be useful as therapeutics for proliferative diseases in which cells divide out of control, and certain viral infections.
The patent furthermore relates to the compounds in their various forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
Cyclacel, a biopharmaceutical company that develop and commercialise novel, mechanism-targeted drugs to treat human cancers and disorders already have the only CDK inhibitor drug in clinical trials.
Seliciclib is a patented purine molecule as opposed to the recently patented agents, which were designed on a pyrimidine chemical scaffold. Seliciclib also belongs to the Cyclin Dependent Kinase (CDK) inhibitor class. By acting on different combinations of Cyclin Dependent Kinases it is possible to stop normal cells growing or to cause cancer cells to commit suicide, otherwise known as apoptosis.
Recent publications have implied that seliciclib has activity in a wide variety of disease models including HIV and inflammatory diseases such as glomerulonephritis. Seliciclib has been tested in Phase I clinical trials in both cancer patients and healthy volunteers and is currently in Phase II clinical trials in patients with non-small cell lung cancer or haematological (blood) cancers.
Dr Robert Jackson, Cyclacel's chief scientific officer said: "We used state-of-the-art technology based on target protein structures to design compounds that hit a variety of cell cycle targets resulting in multiple product opportunities."
"Many of the new compounds have drug-like physicochemical properties. Our objective is to progress one or more of these molecules into clinical trials as soon as possible."
Cancer is the second leading cause of death in the Western World. Solid tumours in particular represent a major public health issue with an incidence of over 2 million people. Breast, colorectal, lung, prostate cancer and leukaemia are the most common cancers. 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.
Anticancer drugs in general are more effective when used in combination. Combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimum time intervals between such doses.
The major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance in early tumour cells which would have been otherwise responsive to initial chemotherapy with a single agent.
An example of the use of biochemical interactions in selecting drug combinations is demonstrated by the administration of leucovorin to increase the binding of an active intracellular metabolite of 5-fluorouracil to its target, thymidylate synthase, thus increasing its cytotoxic effects.