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Cellzome - kinase inhibitors for therapy

Cellzome is a privately-owned biotechnology company which develops new drugs for the treatment of rheumatoid arthritis, multiple sclerosis and chronic inflammatory intestinal diseases at its two company sites in Heidelberg (Germany) and Cambridge (UK).

Cellzome was acquired by GlaxoSmithKline in May 2012.

Cellzome has developed a chemical proteomics method that enables the simultaneous quantification of the effectiveness of chemical substances acting as kinase inhibitors on hundreds of these enzymes in their natural physiological state. The company uses the technology, known as “Kinobeads™“, to advance the development of innovative drug candidates for the treatment of inflammatory diseases.

Kinobeads™ for the kinome

Kinases are enzymes that transfer a phosphate group from ATP to a substrate. More than 500 genes are known to encode this class of enzymes, which are of key importance as targets for drug development. Approximately 30 per cent of the entire research and development budget of the pharmaceutical industry (12 billion US$) are spent in this sector. The active ATP-binding centres of the majority of kinases are very similar. Therefore, low-molecular therapeutics which target this ATP binding site often reveal so-called off-target effects, i.e. effects against other proteins than the target protein of interest. An ideal drug needs to have a high reaction and tissue specificity, which is what Cellzome’s Kinobeads™ technology focuses on, since it enables the simultaneous in vivo analysis of the kinome of entire cells or tissues.

Dr. Gitte Neubauer © Cellzome

"There are eight drugs currently on the market that target kinases - low-molecular molecules such as Gleevec®, Iressa® and Tarceva®," explains Dr. Gitte Neubauer, Vice President Research Operations of Cellzome. "All of these molecules are targeted against tumours. So far, only a few kinase inhibitors have been shown in clinical trials to have an effect against chronic diseases such as rheumatoid arthritis. It is our strategy to use selective kinase inhibitors - hence reducing the risk of undesired side effects - as drugs for the treatment of chronic inflammatory diseases."

Cellzome's most advanced kinase inhibitor programme, with which the company plans to initiate  clinical studies in 2010, targets PI3Kγ, one of four isoforms of class I phosphatidylinositol-3-kinases. PI3Kγ targets a switch of a signalling pathway that is responsible for the targeted movement (chemotaxis) of immune cells towards a chemical attractant. As several laboratories have shown with model systems, the inhibition of the lipid kinase activity of PI3Kγ has a positive effect on autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Cover of Nature Biotechnology no. 25, Sep 2007 © Nature Biotechnology

Other programmes focusing on the discovery of kinase inhibitors of inflammatory diseases are under development or have entered preclinical testing. The KinobeadsTM technology also enables the investigation of kinases (such as Zap-70, mTOR and LRRK2) that cannot be analysed using traditional biochemical screening methods. LRRK2 (leucine-rich repeat kinase 2) is a huge molecule consisting of 2,527 amino acids that plays a role in the pathogenesis of genetic and spontaneous Parkinson's disease.

Cellzome has used KinobeadsTM to investigate the molecular effect of drugs targeting chronic myeloid leukaemia (CML), specifically two drugs that have already received marketing authorisation (Gleevec® manufactured by Novartis and Sprycel® manufactured by Bristol-Myers Squibb) and the effect of a drug that is currently being tested in clinical trials.

Dr. Gerard Drewes, Vice President Discovery Research © Cellzome

The Cellzome team discovered interesting new targets for all three drugs, including two that were inhibited by Gleevec more strongly than the Abelson kinase BCR-ABL, for which the blockbuster drug Gleevec was initially developed (treatment of CML). Dr. Gerard Drewes, Vice President Discovery Technologies of Cellzome and lead author of a study published in Nature Biotechnology (vol. 25, September 2007), which was shown on the cover of the renowned journal, explains: "KinobeadsTM enables us to gain very detailed insights into how kinase drugs function on the molecular level at their natural site of action in cells and tissues. We are not only able to measure the direct interaction of the drug with its native target, but also how this interaction affects the signalling pathways of cells."

Episphere™

Nucleosomes © Cellzome

In analogy to the KinobeadsTM platform, Cellzome has developed a new chemical proteomics technology called EpisphereTM. This technology enables the identification of drug candidates for target proteins that are involved in the epigenetic regulation of inflammatory diseases. Epigenetics refers to genetic alterations of gene expression that are not based on DNA mutations, but which are mediated by specific modifications of DNA and proteins that control the activation and inactivation of gene expression. Epigenetic modifications are acquired during an organism's lifetime and are, at least to a certain extent, inheritable. The active chromosome areas that are important for the expression of genes are arranged like a string of pearls (nucleosomes), in which the DNA thread is wrapped around defined complexes of histone proteins. Epigenetic modifications are mainly controlled by two processes that affect nucleosomes: the methylation and demethylation of DNA through methyl transferases and demethylases, and the acetylation and deacetylation of the histones through histone acetyl transferases and histone deacetylases. These processes are very important for human development and for the development of diseases, for example in the differentiation of immune cells and the expression of genes in the case of inflammations. EpisphereTM  can be used to investigate the binding characteristics of molecules to these enzymes under native conditions in order to identify and develop drugs for treating inflammatory diseases.

Link with science

Cellzone was established in 2000 as a spin-off of the European Molecular Biology Laboratory (EMBL) in Heidelberg. The company acquired the exclusive licence for the tandem affinity purification (TAP) technology discovered by Bertrand Séraphin and Dr. Guillaume Rigaut at the EMBL. TAP enables the isolation of protein complexes and the identification of metabolic pathways. The two researchers were awarded “European Inventors of the Year 2008” by the European Commission and the European Patent Office. In combination with Cellzome’s highly sensitive mass spectrometry of proteins, TAP formed a basis for Cellzome’s first technology platform for the investigation of protein networks, before the company started to focus on investigating the interactions of chemical substances with the proteome. One year after its establishment, Cellzome acquired GlaxoSmithKline’s (GSK) CellMap Unit and, in addition to its company site on the EMBL premises in Heidelberg (Cellzome AG), set up a second operations site in England (now in Cambridge, UK). Cellzome’s Holding Company has its headquarters in the USA. The company employs around 90 people; Tim P. W. Edwards is the company’s CEO.

With the analysis of all protein complexes in the yeast proteome and their publication in Nature in 2002, Cellzome validated its proprietary technology and set new standards in proteomics research. In January 2004, the paper was distinguished as the “all time #1 paper in genetics and genomics” by the “Faculty of 1000”, a renowned database of scientific publications.

Cellzome also attracted great interest with its 2004 publication of the TNFα- (tumour necrosis factor) coupled signalling pathway and its protein interactions. TNFα is a cytokine that triggers a decisive signalling cascade that is involved in inflammatory reactions. In cooperation with Novartis, Cellzome was able to decipher a novel mechanism of action that leads to the inhibition of the Wnt-signalling pathway. This signalling pathway plays an important role in the pathogenesis of cancer, in particular colon carcinomas. The results, recently published in Nature, open up new opportunities in the field of drug discovery.

Partnerships

Cellzome’s unique proteomics technology with which fundamental new insights of medical relevance were obtained, forms the basis for the company’s alliances with leading pharmaceutical companies. Besides financing by top-class international investors, these alliances form the second financial pillar of the company. Cellzome entered a comprehensive strategic partnership with Novartis in which the mapping of signalling pathways and chemical proteomics was used for the identification of new targets and lead substances for numerous indications. This successful four-year partnership came to an end in 2008. Cellzome also has a partnership with Ortho-McNeil Pharmaceutical /Johnson & Johnson PRD focusing on the development of drug candidates for the treatment of Alzheimer’s, which was extended for another two years in 2008. The partnership focuses on lead substances targeting γ secretase, a key enzyme in the formation of β-amyloid, a major component of the pathological deposits in the brain of Alzheimer patients. A second aspect of the cooperation with Johnson & Johnson focuses on the clarification of the Tau protein metabolism, which also plays an important role in the pathogenesis of this disease.

In September 2008, Cellzome entered a strategic global alliance with GlaxoSmithKline (GSK) focusing on the development of clinical drug candidates for the treatment of inflammatory diseases using Cellzome’s Kinobeads™ technology. Only three months after signing the contract, the partners were able to announce that they had reached the first milestone of their partnership, followed by the fourth milestone on 30th September 2009.

Selected literature:

Huang, S.-M. A. et al.: Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614-620 (2009)
Bantscheff, M. et al.: Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotechnology 25, 1035-1044 (2007)
Mallick, P. et al.: Computational prediction of proteotypic peptides for quantitative proteomics. Nature Biotechnology 25, 125-131 (2007)
Gavin, A.-C. et al.: Proteome survey reveals modularity of the yeast cell machinery. Nature 440, 631-636 (2006)
Bouwmeester, T. et al.: A physical and functional map of the human TNF-a/NF-kB signal transduction pathway. Nature Cell Biology 6, 97-105 (2004)
Gavin, A.-C. et al.: Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141-147 (2002)

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