Research

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

Code:

J7-4635

Range:

01. October 2022 - 30. September 2025

Range:

4,26 FTE

Leader:

Lucija Peterlin Mašič

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Ion channels are now considered unconventional, promising oncological targets, whose expression is often altered in cancer cells and which areemerging as critical players in tumorigenesis. The idea of targeting Kv1.3 ion channels directly in mitochondria, whose function critically depends onion fluxes and which are crucial for both cell survival and apoptosis, could change the therapeutic field of cancer research. Resistance to apoptosisis 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 immunecells, which are a central component of the tumour microenvironment, both at the primary site and–more importantly for metastasis–at the distantlocation of the metastatic tumour. Therefore, it is reasonable to postulate that ion channel-based therapies may be beneficial in preventing anderadicating 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 cancerby utilizing mitochondrial Kv1.3 ion channels with proof of principle in in vivo model of pancreatic ductal adenocarcinoma (PDAC). This is veryrelevant because the incidence of PDAC, the third leading cause of cancer-related mortality, is expected to rise. Therapeutic options for patients withmetastatic 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 andMITOCHONDRIOTROPIC BENZAMIDE POTASSIUM CHANNEL KV1.3 INHIBITORS) and newly developed results, which indicate that MitoCan selectiveand potent mitochondrial Kv1.3 inhibitors have a great potential for lead optimization and preclinical development. Mitocan joins internationalpartners that are the discoverers and undisputed leaders in research of cancer and ion channels in cancer together with the most importantSlovenian 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 mitochiondriatargeting moieties (MTMs) and linkers including cleavable and non-cleavable ones. In addition, we will develop improved tumor-specific mtKv1.3inhibitors and nanodelivery systems for mitoKv1.3 inhibitors either alone or in combination with anticancer drugs to increase intratumoral drugconcentration.We believe that the proposed research is creative because the mode of action of the proposed mitoKv1.3 inhibitors (which we have developed in ourlaboratories) is different from current or experimental drugs and offers the prospect of a paradigm shift in the field.