MitoCan - Preclinical development of new Mitochondrial ion channel inhibitors for Cancer therapy

Ion channels are now considered unconventional, promising oncological targets, whose expression is often altered in cancer cells and which are emerging as critical players in tumorigenesis. The idea of targeting Kv1.3 ion channels directly in mitochondria, whose function critically depends on ion fluxes and which are crucial for both cell survival and apoptosis, could change the therapeutic field of cancer research. Resistance to apoptosis is one of the key hallmarks of cancer cells and often arises as a mechanism to escape drug-induced toxicity. Kv1.3 is also important for immune cells, which are a central component of the tumour microenvironment, both at the primary site and–more importantly for metastasis–at the distant location of the metastatic tumour. Therefore, it is reasonable to postulate that ion channel-based therapies may be beneficial in preventing and eradicating metastasis and may be useful in cells that are resistant to classical chemotherapy. MitoCan (Preclinical development of new Mitochondrial ion channel inhibitors for Cancer therapy) is an innovative project aimed at targeting cancer by utilizing mitochondrial Kv1.3 ion channels with proof of principle in in vivo model of pancreatic ductal adenocarcinoma (PDAC). This is very relevant because the incidence of PDAC, the third leading cause of cancer-related mortality, is expected to rise. Therapeutic options for patients with metastatic disease offer only modest survival benefit as PDAC is recalcitrant to both conventional and immune-based therapies. MitoCan is based on two new patent applications (HETEROARYL BENZAMIDE POTASSIUM CHANNEL KV1.3 INHIBITORS and MITOCHONDRIOTROPIC BENZAMIDE POTASSIUM CHANNEL KV1.3 INHIBITORS) and newly developed results, which indicate that MitoCan selective and potent mitochondrial Kv1.3 inhibitors have a great potential for lead optimization and preclinical development. Mitocan joins international partners that are the discoverers and undisputed leaders in research of cancer and ion channels in cancer together with the most important Slovenian research institutes to make a breakthrough in the potential of ion channels for the treatment of cancer. The goal is to develop specific, potent and safe mitochondrial Kv1.3 inhibitors with appropriate PADMET properties (physicochemical properties, absorption, distribution, metabolism, elimination and toxicity). To achieve this goal, we will develop a synthetic platform for different mitochiondria targeting moieties (MTMs) and linkers including cleavable and non-cleavable ones. In addition, we will develop improved tumor-specific mtKv1.3 inhibitors and nanodelivery systems for mitoKv1.3 inhibitors either alone or in combination with anticancer drugs to increase intratumoral drug concentration. We believe that the proposed research is creative because the mode of action of the proposed mitoKv1.3 inhibitors (which we have developed in our laboratories) is different from current or experimental drugs and offers the prospect of a paradigm shift in the field.