Cancer Cell Specific Fe(II)-Clathrochelate-Prodrugs Targeting Advanced Lung Cancer

• Applicant: Professor Dr. Andriy Mokhir
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566641146

Lung cancer is the leading cause of cancer-related deaths worldwide and is frequently diagnosed at advanced stages, when metastases are already present. Non-small-cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases. Although effective treatments exist for NSCLC patients carrying the ROS1 fusion gene, only around 2% of NSCLC patients can benefit from this therapy. Consequently, there is an urgent need for novel therapeutic strategies capable of effectively treating both primary lung cancer and its metastases across a broader patient population. Chronic activation of endoplasmic reticulum (ER) stress pathways is linked to tumor progression and poor prognosis in advanced NSCLC, positioning ER stress as a promising therapeutic target. By increasing the accumulation of unfolded or misfolded proteins in ER-stressed cancer cells, the unfolded protein response (UPR) can be overwhelmed, triggering its shift to a pro-apoptotic program. One clinically approved example is bortezomib, a proteasome inhibitor that enhances ER stress by raising the level of unfolded proteins in the ER. Bortezomib has demonstrated efficacy both as a monotherapy and in combination therapies for NSCLC in clinical trials. However, ER stress-inducing anticancer drugs like bortezomib also affect healthy cells (e.g., neutrophils), severely limiting their therapeutic window. Therefore, developing less toxic ER stress inducers is a crucial next step. The Mokhir group has identified Fe(II) clathrochelate C0, a promising drug that selectively induces ER stress in cancer cells by non-covalently binding to unfolded proteins in the ER, ultimately driving cancer cell death. This mechanism has been demonstrated in vitro across several lung cancer cell lines and in vivo using the Lewis lung carcinoma mouse model, where C0 inhibited primary tumor growth and reduced metastasis. However, the binding of C0 to unfolded proteins is moderate and requires concentrations greater than 10 μM, which limits its anticancer and antimetastatic efficacy. To address this limitation, this project aims to enhance the potency and specificity of C0 by converting it into covalent drugs or prodrugs using three distinct approaches outlined in work packages 1 and 2. These (pro)drugs are designed to form covalent bonds with unfolded proteins in the ER of cancer cells, sparing healthy cells in the process. Proof-of-concept has already been established for two of the three approaches, with representative (pro)drugs synthesized and their mechanisms validated. The third approach involves an electrophilic moiety masked as an aryleboronic acid pinacol ester, a strategy previously employed by the Mokhir group to design aminoferrocene-based prodrugs. This interdisciplinary project is poised to provide critical insights that will help transition Fe(II) clathrochelate-based (pro)drugs toward clinical trials, ultimately offering new therapeutic options for NSCLC patients.

• DFG Programme: Research Grants