Odafosfamide ((S)-OBI-3424) is a highly selective prodrug bis-alkylating agent that is specifically activated by aldehyde-keto reductase 1C3 (AKR1C3), resulting in pronounced cytotoxicity toward tumor cell lines with elevated AKR1C3 expression, and it demonstrates significant antitumor activity in cancers such as liver cancer, non-small cell lung cancer, and leukemia, making it a targeted and mechanistically informative compound for precision oncology research.

Odafosfamide demonstrates cytotoxic effects on liver cancer cells (SNU-475, SNU-449, C3A) with high AKR1C3 protein and RNA expression levels, exhibiting IC50 values of 15 nM, 45 nM, and 5 nM, respectively, as well as on non-small cell lung cancer cells (NSCLC) such as NCI-H1944, NCI-H2228, NCI-H1755, NCI-H1563, NCI-H2110, and NCI-H1792, with IC50 values of 2.3 nM, 0.21 nM, 8.2 nM, 2.5 nM, 1.1 nM, and 4.5 nM. Additionally, odafosfamide shows potential anti-leukemic activity against 19 leukemia cell lines representing B-ALL, T-ALL, and ETP-ALL, with IC50 values of 60.3 nmol/L, 9.7 nmol/L, and 31.5 nmol/L, respectively.

In extensive preclinical models, Odafosfamide demonstrates potent antitumor efficacy. In orthotopic liver cancer (HepG2) xenografts, intravenous (i.v.) administration at 5 mg/kg (weekly for 2 weeks) achieved complete tumor regression with a Tumor Growth Inhibition (TGI) of 101.2%. In castration-resistant prostate cancer (CRPC) models (VCaP xenografts), a 5 mg/kg dose resulted in a TGI of 148%, indicating significant tumor shrinkage, an effect further enhanced when combined with Abiraterone. In pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) patient-derived xenograft (PDX) models, intraperitoneal (i.p.) injection at 2.5 mg/kg (weekly for 3 weeks) induced substantial disease regression [1][2].