Thursday, April 3, 2025
4/3/2025
Development of anti-cancer probes targeting ferroptosis pathway - ABSTRACT. Conventional cancer chemotherapy typically induces apoptosis, but many tumors become resistant to these agents by inducing anti-apoptotic pathways. Therefore, anticancer therapies targeting non-apoptotic pathways, such as ferroptosis, is an exciting field that offer great potential for overcoming cancer chemo-resistance. Our group is particularly focused on the development of a selective therapeutic strategies based on the ferroptosis pathway that could complement the existing therapeutics to target hard-to-treat cancers such as non-small cell lung cancer (NSCLC) that are resistant to conventional therapies. Using a two-stage screening paradigm, the PI engineered a drug-like nanomolar potent ferroptosis inducer named TKD1079. This compound has high mouse microsomal stability (T1/2 = 402 min) and low plasma clearance (Clint = 1.7 μL/min/mg). Mechanistically, TKD1079 induces ferroptosis selectively instead of apoptosis by causing glutathione peroxidase 4 (GPX4) depletion. TKD1079 triggered ferroptosis in both human fibrosarcoma HT-1080 and adenocarcinoma lung NCI- H23 cancer cell lines while sparing normal, healthy cells (Beas-2B) with 500-fold therapeutic index (TI). Cell death induced by TKD1079 was fully suppressed by the canonical ferroptosis inhibitors deferoxamine and - tocopherol, indicating that it specifically induces ferroptosis. However, the solubility of TKD1079 is low (1.3 M in PBS) and engineering TKD1079 analogs with improved drug like properties including better solubility is required for in vivo studies. Our central hypothesis is that a version of TKD1079 that preserves pro-ferroptosis activity but with increased potency, solubility and stability will be useful to overcome apoptosis/chemo-resistance in hard-to-treat cancers such as NSCLC. We will address this hypothesis by exploring two specific aims: (1) SAR study of first-in-class ferroptosis inducers based on TKD1079 scaffold, and (2) identify the optimal top 2-3 TKD1079 analogs that drive ferroptosis selectively in vitro with improved pharmaceutical properties. Successful completion of this proposed work will facilitate the development of a first-in-class TKD1079 analogs that retain the many positive features of TKD1079 and possess improved solubility for lung cancer therapeutics that trigger ferroptosis and will propel their development towards pre-clinical application.
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