Projects / Programmes
New anticancer leads for emerging cancer target potassium ion channels hEag1 and its validation in lymphoma tumors
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| B740 |
Biomedical sciences |
Pharmacological sciences, pharmacognosy, pharmacy, toxicology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
cancer, ether-a-gogo potassium channel (Eag, Kv1.10); anticancer leads; computer-aided drug design (CADD), medicinal chemistry
Researchers (16)
Organisations (2)
Abstract
Cancer remains an important cause of mortality and economic losses worldwide. Non-Hodgkin lymphoma (NHL) is among the 10 most-frequent forms of cancer in the EU and have the bad prognosis with the current therapeutic options. NHLs are a very heterogeneous group of disorders that comprise some very aggressive subtypes, with no standard for therapy. Even for individuals affected by diffuse large B-cell lymphoma, the most common NHL type in the western world, cure can be obtained in only two thirds of cases. For an improved cancer therapy approach, a permanent need for the discovery of new-generation, refined anticancer agents is needed, as well as the elucidation of novel cancer targets.
These insights highlight the unmet medical need for development of new therapeutic strategies. Exploitation of genuinely novel classes of cancer targets with new mechanisms of action provides great opportunities for the discovery of new anticancer drugs for NHL. Targeting the voltage-gated potassium ion channels and hEag1 in cancer is one of the most exciting recent advances in cancer biology. In addition, combined modulation of two or more selected cancer targets (e.g., inhibitors of hEag1 in combination with known anticancer drugs) might lead to synergistic anticancer effects that have not yet been uncovered. The Project is designed to grow the cancer drug target space by targeting underexplored target with new mechanisms of action: voltage-gated potassium channels hEag1.
The Project Consortium aims to discover new selective small-molecule inhibitors of hEag1 using drug-design methods and original platform for electrophysiological and anticancer evaluation. Proposed Project is an interdisciplinary research project covering all steps of anticancer lead discovery. These include: understanding the genetic and biological basis of cancer, design strategies of new lead compounds, organic synthesis, innovative pharmacological evaluation, and hit-to-lead optimisation. The overarching goal is to discover first-in-class leads for hEag1 cancer target and to broaden treatment possibilities for NHL.
Most of the progress in cancer biology of hEag1 cancer target and their new modulators have been achieved by academic and research institutions that are part of the proposed Project Consortium. Therefore, the expertise for new hEag1 lead discovery, which have not been integrated into any industrial anticancer drug discovery pipelines yet, already exist through Europe, but is rather dispersed in various European research institutions. To bridge this gap and to create a large innovative force for specific hEag1 anticancer lead discovery, we have designed an interdisciplinary research project that involves all phases of anticancer lead discovery.
The Consortium consists of two excellent academic partners University of Ljubljana and KU Leuven, who are world-class medicinal chemists and toxicologists, and three world-renowned cancer institutes National Institute of Biology (Slovenia), Institute of Oncology Research (Switzerland) and Max Planck Institute of Experimental Medicine (Germany), who will integrate biological, genomic and molecular approaches with translational studies in lymphoid tumours. As the work will be performed within word-class European institutions that cover all of the important aspects of lead discovery, this will result in medically relevant research and in translation of the results into practice. This multidisciplinary Project will be of great interest for the pharmaceutical industry.
Significance for science
Cancers remain one of the leading causes of death worldwide, and one of the main limitations of current anticancer therapies involves chemo-resistance to known anticancer drugs. The perspective concept of targeting voltage gated potassium ion channels as cancer target has gained considerable attention in the last years. Voltage-gated potassium ion channel hEag1 has earned its clinical relevancy as a potential target in cancer research by the remarkable observation that, in sharp contrast to its almost non-existing extra neural expression in native tissues, abundant hEag1 expression has been reported in over 70% of tumours investigated.
The Project platform brings distinctive elements of innovative aspects and originality to anticancer lead discovery: (i) The concept of targeting voltage-gated potassium ion channels hEag1 in cancer is one of the most exciting recent advances in Cancer Biology. The Prof. Luis Pardo Lab (partner in this project) pioneered this novel research field, and was the first to show therapeutic potential of hEag1 inhibitors in cancer. (ii) Validated and selective 3D pharmacophore model for hEag1 will be used for hit finding and hit-to-lead optimisation studies of new hEag1 inhibitors. (iii) One of the key strengths of the Project is the original platform for testing anticancer potential of new hEag1 inhibitors. (iv) The ambitious interdisciplinary project proposed herein aims to discover first-in-class leads for the hEag1 cancer target, to enable new treatment options of non-Hodgkin Lymphoma and other cancers.
While the project stands on solid ground, the discovery of new leads requires combined expertise in cancer biology, medicinal chemistry, toxicology and pharmacology. As there is hardly enough expertise in any single area of the Europe, proposed Project addresses one of the major drawbacks in the discovery of new leads; namely, the scattered expertise around Europe. As the work will be performed within word-class European institutions that cover all of the important aspects of lead discovery, this will result in medically relevant research and in translation of the results into practice. Thus, the Project is not only innovative, original and timely, but also medically relevant.
The results of this research Project will be new anticancer leads for emerging and unexplored cancer target hEag1, and its validation in lymphomas tumours. In addition, the goal is also to find new combinations (e.g., new hEag1 inhibitors and known anticancer drugs), which might lead to synergistic effects that have not yet been discovered.
A combination of excellent partners in the proposed Project will strengthen the innovative activities and enhance the cooperation and knowledge and expertise transfer between two universities and three world-renowned institutes. It can be expected that new anticancer leads and concepts that will result from the proposed Project will be welcomed by drug research companies.
Significance for the country
Cancers remain one of the leading causes of death worldwide, and one of the main limitations of current anticancer therapies involves chemo-resistance to known anticancer drugs. The perspective concept of targeting voltage gated potassium ion channels as cancer target has gained considerable attention in the last years. Voltage-gated potassium ion channel hEag1 has earned its clinical relevancy as a potential target in cancer research by the remarkable observation that, in sharp contrast to its almost non-existing extra neural expression in native tissues, abundant hEag1 expression has been reported in over 70% of tumours investigated.
The Project platform brings distinctive elements of innovative aspects and originality to anticancer lead discovery: (i) The concept of targeting voltage-gated potassium ion channels hEag1 in cancer is one of the most exciting recent advances in Cancer Biology. The Prof. Luis Pardo Lab (partner in this project) pioneered this novel research field, and was the first to show therapeutic potential of hEag1 inhibitors in cancer. (ii) Validated and selective 3D pharmacophore model for hEag1 will be used for hit finding and hit-to-lead optimisation studies of new hEag1 inhibitors. (iii) One of the key strengths of the Project is the original platform for testing anticancer potential of new hEag1 inhibitors. (iv) The ambitious interdisciplinary project proposed herein aims to discover first-in-class leads for the hEag1 cancer target, to enable new treatment options of non-Hodgkin Lymphoma and other cancers.
While the project stands on solid ground, the discovery of new leads requires combined expertise in cancer biology, medicinal chemistry, toxicology and pharmacology. As there is hardly enough expertise in any single area of the Europe, proposed Project addresses one of the major drawbacks in the discovery of new leads; namely, the scattered expertise around Europe. As the work will be performed within word-class European institutions that cover all of the important aspects of lead discovery, this will result in medically relevant research and in translation of the results into practice. Thus, the Project is not only innovative, original and timely, but also medically relevant.
The results of this research Project will be new anticancer leads for emerging and unexplored cancer target hEag1, and its validation in lymphomas tumours. In addition, the goal is also to find new combinations (e.g., new hEag1 inhibitors and known anticancer drugs), which might lead to synergistic effects that have not yet been discovered.
A combination of excellent partners in the proposed Project will strengthen the innovative activities and enhance the cooperation and knowledge and expertise transfer between two universities and three world-renowned institutes. It can be expected that new anticancer leads and concepts that will result from the proposed Project will be welcomed by drug research companies.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
