Project Details
Projekt
Substitutive Chemotypes as Tools for the Selective Induction of Ferroptosis in Cancer Cells
Applicant
Dr. David Konrad
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461576077
Lung cancer is the leading cause of cancer-related mortality worldwide, whereas 85% of all cases are Non-Small Cell Lung Cancer (NSCLC). An emerging drug target in NSCLC is the kirsten rat sarcoma viral oncogene (KRAS), due to the G12C activating mutation which is present in about 14% of patients and can be selectively labelled by the small molecule inhibitors AMG510 and MRTX849. Preclinical studies have provided promising evidence that the inhibition of mutant KRAS using AMG510 leads to an inflammatory immune response within the tumor microenvironment. However, the high adaptability of NSCLCs leads to the rewiring of KRAS signaling, which may render the drug inactive over time. To avoid these evasive mechanisms of cancer, it is necessary to develop therapeutics that directly kill the cancer cells. In this regard, the discovery that cancer cells are highly susceptible to ferroptosis, an atypical oxidative cell death process, which is induced through the inhibition of the GPX4–GSH–cysteine pathway, has uncovered an untapped therapeutic vulnerability. The use of state-of-the-art GPX4 inhibitors in animals, however, leads to systemic toxicities due to ferroptosis-sensitive cells that exist e.g. in the central nervous system, the brain and the kidneys. We aim to develop a new mechanism to impart GPX4 inhibitors with selectivity towards cancer cells to enable their use in cancer treatment. Our strategy is to build bifunctional constructs that harness the selectivities of AMG510 and/or MRTX849 towards G12C mutants of KRAS to deliver GPX4 inhibitor prodrugs into cancer cells and release them in their active form. To this end, we plan on reprogramming the reactivity of the electrophilic acrylamide handle that covalently links the KRAS G12C inhibitors to their target protein by extending its reactivity from Michael additions to SN2’ reactions and/or addition-elimination sequences. This can be achieved by appending leaving groups either at the β-position or via a methylene group at the α-position. If these ‘substitutive chemotypes’ are incorporated into the AMG510 and/or MRTX849 backbone in place of the original acrylamide, the leaving group serves as hinge to append a GPX4 inhibitor prodrug. This prodrug can be released and activated through a reaction between the drug construct and the mutated KRAS. We envisage that the newly established bifunctional chemotherapeutics complement the selectivity and the ability to induce antitumor immunity that are inherent in KRAS G12C inhibitors with the ability of GPX4 inhibitors to induce ferroptotic cell death into one small molecule therapeutic.
DFG Programme
Priority Programmes
