Analog of pleuromutilin identified for multiple cancers

INDICATION: Breast cancer; colorectal cancer; ovarian cancer; pancreatic cancer; solid tumors

Cell culture and mouse studies identified a thioredoxin inhibitor that could help treat breast, ovarian, pancreatic and other cancers. Chemical synthesis and testing of analogs of the natural product pleuromutilin in a human ovarian cancer cell line yielded a compound, ferroptocide, that inhibited growth with an IC₅₀ of 1.6 μM, and cell-based binding assays identified thioredoxin as the compound's probable target. In primary cancer cells from patients with breast, gastrointestinal, lung, ovarian pancreatic or other cancers, ferroptocide decreased growth compared with cisplatin, 5-fluorouracil (5-FU), etoposide and procaspase-activating compound 1 (PAC-1). In human pancreatic and colorectal cancer cell lines, the compound decreased growth compared with the DNA alkylator methylnitronitrosoguanidine or the cytotoxic natural product staurosporine. In a mouse model of triple-negative breast cancer (TNBC), the compound decreased tumor volume compared with vehicle. Next steps could include testing ferroptocide in mouse models of other cancers...