Development of anti-cancer probes targeting ferroptosis pathway

University Of Massachusetts Amherst, Amherst MA

Investigators

Abstract

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.