Project: Development of novel epigenetic cancer therapies based on the design and synthesis of new non-covalent DNMT inhibitors.
This Project aims at the design, synthesis and pharmaceutical development of a new family of anticancer molecules by inhibiting an enzyme called DNA methyltransferase or DNMTs. For this purpose, IkerChem and the Fraunhofer Institute for Cell Therapy and Immunology (IZI) will join in a consortium, where IkerChem will carry out the design and synthetic activites, as well as the enzymatic validation and in vivo toxicological studies. On the other hand, the Fraunhofer Institute will carry out the biological in vitro (tumour cell lines) and in vivo (xenotransplanted mice) screening studies, along with the screening of biomarkers in DNMT inhibitor treated tumour stem cells and in vitro toxicology and inmunotoxicology studies._x000D_The selected targets for the development of the compounds of the present proposal are the DNMTs, a family of enzymes that are responsible for the addition of a methyl group to one of the bases (cytosine) that constitute the coding sequence of DNA, which can lead to the prevention of the gene transcription. These epigenetic alterations may lead to an increased susceptibility to certain diseases, such as cancer or psychiatric disorders. In cancer, DNA methylation patterns has two fazes: _x000D_- On the one hand, hypermethylation of promoter regions of cancer-related genes is observed, which can lead to silencing of critical genes normally involved in tumour suppression, such as those involved in DNA reparation, in cell cycle regulation, apoptosis and metabolism of carcinogens. Inactivation of the expression of these genes, due to the methylation of the promoter regions of such genes, has been observed in cancer cell lines and human tumours, such as ovarian and breast cancers. _x000D_- On the other hand, global hypomethylation of the DNA can occur in parallel with the hypermethylation, which can lead to chromosomal instability and the activation of oncogenes._x000D_Therefore inhibition of the DNMTs is emerging as an important therapeutic area, both in oncology and other diseases, such as neurodegenerative disorders (schizophrenia, bipolar disorder, Alzheimer, etc.). Currently, several DNMTs inhibitors are in clinical phases, whose molecular characteristics and development stage is listed below, as well as their CO limitations: _x000D_a) Covalent trapping of DNMT1 through incorporation into DNA, such as 5-Azacitidina (Vidaza) and Decitabine (Dacogen). Both have been approved by the FDA for therapeutic use. One limitation of these nucleosides analogues is the requirement for DNA incorporation, which can lead to a nonspecific cytotoxicity and high toxic side effects._x000D_b) Interruption of the biding site of DNMT1 to DNA, such as procaine (phase II). A major drawback of these drugs is the high concentration required for their demethylating activity, which can cause undesired toxic effects._x000D_c) Non-covalent blocking of DNMT1 catalytic active site, such as EGCG (phase II). However, the EGCG generates hydrogen peroxide, which contributes to its toxicity in human cell lines._x000D_d) Degradation of DNMT1, such as SGI-1027 (preclinical). _x000D_e) Suppression of DNMT1 expression, such as the antisense MG-98 (phase I). This compound has shown toxic effects in clinical trials._x000D_There is also evidence of synergies between DNMTs and histone deacetylase (or HDACs). HDAC enzymes catalyze the removal of the acetyl modification on lysine residues of the core nucleosomal histones H2A, H2B, H3 and H4, and other non-histone proteins such as p53, playing an important regulatory role in gene transcription, as histones form a scaffold around which a cell's DNA is wrapped. Hypoacetylation of histones is associated with the repression of gene transcription, whereas acetylated histones are associated with the activation of gene transcription. Alterations in HDACs have been identified in tumour cells and may contribute to the altered gene expression found in many cancers. HDAC inhibitors can induce differentiation, cell cycle arrest or apoptosis in tumour cells and can inhibit tumour growth. IkerChem has been developing several HDAC inhibitors within the framework of another project. _x000D_In summary, the current state of the art shows an excellent business opportunity for the development of DNMT inhibitors, as pharmaceutical companies are looking for alternative drugs with lower toxicity and better bioavailability, and most of the existing compounds that are currently on the market or in clinical trials present toxicity problems or have a poor pharmacokinetic profile. Indeed, several pharmaceutical companies have shown a strong interest in our epigenetic program and have encouraged us to develop a family of DNMT inhibitors._x000D_
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Acronym
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FINDNMT
(Reference Number: 6380)
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Duration
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01/06/2011 - 31/05/2014
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Project Topic
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This Project's CO objective is to design synthesis and develop a new family of anticancer molecules by inhibiting an enzyme called DNA methyltransferase or DNMTs. These molecules will present a low toxicity as, unlike the actual approved drugs, they are not going to incorporate to the DNA.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 6
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Project partner
