molecules of the month

A diaziridine-based tumor-activated prodrug for AKR1C3-expressing cancers from a defunct Bay Area biotech. OBI-3424 (formerly TH-3424) is a tumor-activated prodrug in Ph. II that releases DNA-crosslinking diaziridine phosphamide (remniscent of thioTEPA) upon activation by the NAD(P)H-dependent aldoketoreductase, AKR1C3, which is differentially expressed in many cancers. The molecule was originated at Threshold Pharma in South San Francisco, a company led by former UCSF Vice Chancellor Barry Selick that focused initially on hypoxia-activated prodrugs like EGFRi-releasing tarloxitinib bromide (TH-4000) and nitroimidazole mustard evofosfamide (partnered with Merck KGaA but returned after Ph. III failure). The developers believe that OBI-3424 could distinguish from traditional phosphamide mustard agents, which alkylate and cross-link DNA at guanine at N7, by being more specific for tumors that express…