BIMOCLOMOL - A NONTOXIC, HYDROXYLAMINE DERIVATIVE WITH STRESS PROTEIN-INDUCING ACTIVITY AND CYTOPROTECTIVE EFFECTS

Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes w hose products are specifically dedicated to protect cellular functions against stress. One of the best known mechanisms protecting cells fro m various stresses is the heat-shock response which results in the ind uction of the synthesis of heat-shock proteins (HSPs or stress protein s)(1-3). A large body of information supports that stress proteins - m any of them molecular chaperones(4-8) - are crucial for the maintenanc e of cell integrity during normal growth as well as during pathophysio logical conditions(9-11), and thus can be considered ''homeostatic pro teins.'' Recently emphasis is being placed on the potential use of the se proteins in preventing and/or treating diseases(12-14). Therefore, it would be of great therapeutic benefit to discover compounds that ar e clinically safe yet able to induce the accumulation of HSPs in patie nts with chronic disorders such as diabetes mellitus, heart disease or kidney failure. Here we show that a novel cytoprotective hydroxylamin e derivative, [2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridinecarboxim idoil-chloride maleate, Bimoclomol(15), facilitates the formation of c haperone molecules in eukaryotic cells by inducing or amplifying expre ssion of heat-shock genes. The cytoprotective effects observed under s everal experimental conditions, including a murine model of ischemia a nd wound healing in the diabetic rat, are likely mediated by the coord inate expression of all major HSPs. This nontoxic drug, which is under Phase II clinical trials, has enormous potential therapeutic applicat ions.