Cyclacel / Novel Anticancer Drugs Inhibiting Plk1
BOSTON, Nov. 18 /PRNewswire/ -- Cyclacel Limited, the UK-based biopharmaceutical company, announced this week that it discovered a series of novel, potent, and highly selective drugs inhibiting human Polo-like kinase 1 (Plk1). Plk1 plays a central role in the regulation of the cancer cell cycle at the stage of mitosis or cell division. Prof. David Glover, Chief Scientist of Cyclacel's Polgen division, first discovered Plk in 1988. The Plk1 inhibitors were discovered using Cyclacel's state-of-the-art rational drug design technology. Further details of their discovery will be reported this week in a Cyclacel scientific communication, during the American Association for Cancer Research - National Cancer Institute - European Organization for Research and Treatment of Cancer (AACR-NCI-EORTC) joint conference in Boston, Massachusetts.
Spiro Rombotis, CEO of Cyclacel said, "The Plk1 inhibitors are the latest additions to our growing pipeline of cell cycle modulators, which includes clinical, preclinical and discovery stage programs. The discovery of Plk1 inhibitors, the first program from our Polgen collection of mitotic control targets to reach small molecule chemistry, underscores the productivity of our discovery team. We reported similar progress in our CYC400 second-generation CDK inhibitor program earlier this year."
Plk1 is a member of the Plk family of mitotic control genes that is highly conserved in evolution across various species such as fruit flies and humans. Plk1 has been shown to be overexpressed in many human tumours, such as breast, colorectal, non-small cell lung, oesophageal and ovarian cancers. It plays a central role in the regulation of the cancer cell cycle. Among other functions, Plk1 is thought to regulate initiation, progression and exit from mitosis, the stage when cancer cells divide. Consequently, blocking Plk1 in cancer cells prevents their division or mitosis. The taxanes, highly successful drugs that are widely used in clinical practice to treat cancer, also work by blocking mitosis. However, these drugs cause considerable side effects upon normal, non-dividing cells especially in the nervous system. Plk inhibitor drugs specifically target dividing cells and may be able to avoid the undesirable toxicities of the taxanes. Despite the attractiveness of Plk1 as an anticancer drug target, little progress has been reported with regard to the discovery of chemical inhibitors of the Plk1 kinase.
Cyclacel revealed that its previously undisclosed Plk1 drug discovery program succeeded in generating multiple novel inhibitors. Certain of these demonstrated high specificity and potency at the low nanomolar level. Scientists at Cyclacel's Dundee, Scotland and Cambridge, England laboratories and collaborators at the University of Edinburgh constructed and validated a homology structure model of Plk1's kinase domain using inhibitors of its ATP-binding site from Cyclacel's in house kinase inhibitor collection.
Virtual screening of chemical compound libraries using LIDAEUS(TM) high-throughput docking software identified hits based on a novel pharmacophore. Further analogue synthesis in conjunction with advanced computational methods resulted in definition of a structure-activity relationship for this new pharmacophore. Testing members of this series against an extensive panel of protein kinases revealed that they show almost complete selectivity for Plk1 and do not interact with other kinases such as CDKs. In addition these compounds were shown to have favourable in vitro anti- tumour effects on several cell lines and exhibit a phenotype consistent with mitotic arrest. Following optimisation a lead inhibitor was obtained with IC50 potency against Plk1 in the low nanomolar range.
Professor Sir David Lane, Cyclacel's Chief Scientific Officer, said, "Acceptance of the role of Plk1 as a very important mechanism in regulating cancer cell mitosis is rising rapidly. In addition to the advantage of Professor David Glover's insight in Plk1 biology, we benefited by the application of cutting-edge drug design approaches developed by Cyclacel and our collaborators to discover these exciting drug candidates. Plk1 is but one crucial target to arise from recent advances in cell cycle biology. The cell cycle field continues to evolve and presents vast opportunities for designing innovative pharmaceuticals to treat cancer and other serious diseases."
Professor David Glover, Chief Scientist of Cyclacel's Polgen division, said, "It is most gratifying and exciting to see work progress from the initial discovery of a mitotic regulator in basic biological research to the development over a decade later of small molecules with promising potential as anticancer treatments."
Dr Bob Jackson, Cyclacel's Executive Director of Research and Development, said, "The discovery of promising Plk1 inhibitors demonstrates the breadth of our technology and the talent of our team. This is a challenging area for designing new anticancer drugs possibly because no crystal structure has been published as yet. We nevertheless made rapid progress with an innovative homology model and used advanced techniques to identify this novel series. If Plk1 inhibitors make it to the clinic, we would expect to use our growing biomarker toolkit to support their clinical evaluation just as we are doing with our lead agent CYC202 now in Phase IIa clinical trials."
About Cyclacel (www.cyclacel.com)
Cyclacel is a biopharmaceutical company that designs and develops small molecule drugs that act on cell cycle regulators to stop uncontrolled cell division in cancer and other diseases involving abnormal cell proliferation. Cyclacel discovery integrates cell cycle biology with a library of gene-based targets, RNAi functional genomics, chemogenomics and clinical biomarker technologies to rapidly deliver new drugs. The most advanced of Cyclacel's 8 research and development programs is CYC202, a Cyclin Dependent Kinase Inhibitor (CDKI), in Phase IIa trials for breast and lung cancer. CYC202 is also being explored for use in glomerulonephritis, an inflammatory disease associated with kidney cell proliferation. CYC400, 2nd generation CDKIs, and CYC381, clotrimazole analogues, acting on the cancer cell cycle are in preclinical development. Cyclacel has entered into corporate alliances with AstraZeneca, CV Therapeutics, Lorus Therapeutics and a top 5 pharmaceutical major all in the oncology field.
Notes to Editors:
American Association for Cancer Research - National Cancer Institute - European Organization for Research and Treatment of Cancer (AACR-NCI-EORTC) Conference, Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications; November 17-21, 2003; Boston, Massachusetts (http://www.aacr.org/2003mtct.asp).
Abstract Number A191: Structure-based ligand discovery and anti-tumour effects of Polo-like kinase-1 ATP-competitive inhibitors. Authors : C McInnes, M Mezna, G Griffiths, J Grabarek, C Midgely, J O'Boyle, C Meades, A Osknowski, J Melville, A Plater, N Pandit, P Taylor, D Zheleva, S Wang, R Jackson, D Glover, D Lane, M Walkinshaw and P Fischer. 18 November 20, Hall C-D, Hynes Center in Boston 12.30 - 2.30pm.
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