Mechanism of action of the hypoxia-activated irreversible pan-HER inhibitor SN29966

Abstract

Hypoxia occurs in most human tumors and is associated with disease progression, treatment resistance and poor patient outcome. We have developed the hypoxia-activated prodrug SN29966, designed to release the irreversible pan-HER inhibitor SN29926, following one-electron reduction by hypoxic cells (Smaill et al, Mol Cancer Ther., 2009; 8(12 Suppl), C46). Pharmacokinetic (PK) studies in nude mice bearing A431 tumor xenografts indicated SN29966 has a long tumor half-life (>3 days) and releases SN29926 in tumors. SN29966 demonstrated single agent activity in nude mice bearing A431 and SKOV3 xenografts, inducing striking tumor regressions in both models (Patterson et al, Mol Cancer Ther., 2009; 8(12 Suppl), B76). PR509 and PR610, clinical candidates developed from SN29966, are currently undergoing comparative evaluation with Phase I trials anticipated in early 2012.