[en] Full text: Methylproamine is the current lead compound of a new class of DNA-binding radioprotectors being developed in the Research Laboratories at the Peter MacCallum Cancer Centre in Melbourne. The salient features of methylproamine are its radioprotective potency and the generic nature of the apparent radioprotective mechanism. Like the 'classic' aminothiol radioprotectors exemplified by amifostine, methylproamine suppresses the initial radiochemical damage induced in DNA by ionising radiation. However, survival curve studies with cultured cells have demonstrated that methylproamine is 100-fold more potent than WR1065, the active metabolite of amifostine. The radioprotective mechanism seems to involve reduction by the DNA-bound drug of transient radiation-induced oxidising species on DNA. This mechanism implies some electron transfer along DNA, from the DNA-bound drug to the oxidising species. In vivo radioprotection of mouse lung, GI tract and bone marrow has been demonstrated following systemic administration of methylproamine to mice. The commercial potential of radioprotectors resides in two distinct arenas. Until recently, most of our efforts have focused on the use of methylproamine to protect normal tissues in cancer radiotherapy patients, but a quite different opportunity arises from the imperative to develop countermeasures to the threat of radiation terrorism. Our prospects in both arenas have been lifted by the results of synthesis and screening of a pilot library of ∼50 methylproamine analogues, promising the emergence of new lead drugs. In particular, although methylproamine is a potent radioprotector, at higher concentrations it becomes cytotoxic, but one member of the pilot library shows a wider efficacy 'window'. We plan to continue this lead optimisation process by synthesis and screening of a much larger library of analogues, and we are seeking the support of a commercial partner