CYCLACEL REPORTS PROGRESS WITH 2ND GENERATION CDK INHIBITOR.
Specific details of several of the new agents will be presented by Cyclacel at the 94th Meeting of the American Association for Cancer Research taking place in Washington, DC in a few weeks. A report on the complex crystal structures of these compounds was recently published in the journal Structure.
"The identification of promising new compounds from our CYC400 platform is a strong validation of our structure-based drug design approach based on in silico screening," said Sir David Lane, chief scientific officer of Cyclacel. "Our genes-to-drugs program has generated a range of active molecules with exquisite specificity against the CDK enzyme that are over a thousand times more potent than our previous series. Work is under way to select new development candidates from this set. The outstanding potency of these new drugs suggests that they may demonstrate improved performance over other published CDK inhibitors."
The CYC400 CDK inhibitor series has emerged from a pyrimidine basic chemical structure or pharmacophore. This chemical scaffold differentiates these compounds from Cyclacel's CYC200 purine series, which generated Cyclacel's first clinical candidate, CYC202, now undergoing Phase II trials.
CYC202 (R-roscovitine) is a novel cell cycle drug belonging to the Cyclin Dependent Kinase (CDK) inhibitor class. CDK inhibition is an important new approach in the quest for drugs that target the molecular mechanism of the body's own cancer stopping genes. In preclinical studies CYC202 demonstrated high specificity against the CDK target. CYC202 is supplied in capsules and is the first drug in its class that is available by mouth. Results of an initial Phase Ia clinical trial suggest that CYC202 appears to be orally available in man and well tolerated after a single dose with biodistribution that is consistent with preclinical results. CYC202 is currently in Phase IIa trials for breast and lung cancer. CYC202 has also completed a Phase I trial in healthy volunteers and is being explored for use in glomerulonephritis, a disease of renal cell proliferation. 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. Tumor 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 tumor suppressor gene behavior and cause cancer cells to die. There are several CDK enzymes that appear to be promising targets. Scientific publications and Cyclacel's in house data suggest that inhibition of CDKs appears to be directly linked with programed death of cancer cells through apoptosis. The discovery of CDKs and cyclins and their role in checkpoint control of the cancer cell cycle has been honored with the 2001 Nobel Prize for Medicine and Physiology.
Spiro Rombotis, CEO of Cyclacel said. "The emergence of these novel CDK inhibitors with superior properties illustrates the talent of our scientists and the cutting edge technology used at Cyclacel. These exciting research developments are part of our business strategy of building a unique pipeline of innovative compounds from genomic targets in rapid, industrial progression. Our ability to inform drug design by harnessing observations made in clinical trials and other parts of our business, such as our Polgen division, is unusual for a young company and suggests an important competitive advantage of our business model. In the months to come we expect to report further progression of both our drug discovery and our clinical development pipeline."
About the CYC400 Drug Discovery Platform
Cyclacel's CYC400 drug discovery program is the product of the company's integrated suite of structure-based drug design tools and expertise. Cyclacel obtained initial computer hits using a compound set selected by its proprietary LIDAEUS in silico screening technology. The company achieved active hit rates of 27% in biochemical assays compared with a 5% hit rate from randomly selected compounds. In the subsequent step of lead optimisation of approximately 350 compounds Cyclacel scientists employed detailed biochemical, cellular, and pharmacokinetic analysis supported by intensive X-ray crystallography studies. Co-crystal structure solution of initial candidates docked in the active site of the CDK enzyme guided parallel synthesis iterations that resulted in analogues with high CDK selectivity, nanomolar potency in cells and profound cell cycle effects. A recent publication in the high impact journal Structure described the development of LIDAEUS[TM] and its application in the discovery of the CYC400 series molecules.
The world-leading cell cycle biology expertise of Polgen division scientists further benefited compound selection from the CYC400 drug discovery program. Mechanism of action studies employed, among other techniques, Cyclacel's state-of-the-art RNA interference technology (used to understand the function of genes) using knock down of cell cycle proteins. This RNAi technology is the subject of a recently announced collaboration between Cyclacel, a leading pharmaceutical company, Cancer Research Technology and the University of Cambridge with the objective of designing new disease models.
Cyclacel is a biopharmaceutical company that designs and develops small molecule drugs that act on key cell cycle regulators to stop uncontrolled cell division in cancer and other diseases involving abnormal cell proliferation. The company's discovery engines integrate core cell cycle expertise with a large library of proprietary gene-based targets, state-of-the-art molecular biology, RNAi functional genomics and computational chemistry to rapidly deliver new drug candidates. Cyclacel has five research and development programs underway. Most advanced is CYC202, a Cyclin Dependent Kinase (CDK) inhibitor, currently in Phase II trials for cancer. CYC202 has also completed a Phase I trial in healthy volunteers and is being explored for use in glomerulonephritis, a disease of renal cell proliferation. Cyclacel has a corporate alliance with AstraZeneca to develop a specific Cyclin Groove Inhibitor (CGI) for cancer.
For more information, visit http://www.cyclacell.com.
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|Date:||Jul 1, 2003|
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