Reduction of OBI-3424 by AKR1C3 in the presence of NADPH to produce the cytotoxic agent OBI-2660.
NSCLC, human hepatocellular carcinoma, death
SOLID TUMORS, CYTOTOXICITY, NSCLC
In the presence of NADPH, reduction of OBI-3424 is mediated by AKR1C3 to release the cytotoxic moiety OBI-2660, which is an aziridine bis-alkylating agent, leading to crosslinking of DNA at the N7 (or O6) position of guanine and subsequent cell death. AKR1C3 aldo-keto reductase family 1 member C3.In a study using 11 human hepatocellular carcinoma cell lines and 10 human NSCLC cell lines, OBI-3424 exhibited enhanced cytotoxicity in the cell lines with AKR1C3 overexpression compared with the cell lines with low (protein expression ≤0.21 and RNA expression ≤0.19 LogWe report the results of a Phase 1, first-in-human, sequential dose-escalation study of OBI-3424 in patients with advanced solid tumors. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OBI-3424 as a single agent.