Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications

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Abstract The complications of diabetes, particularly impaired wound healing and diabetes-associated nephropathy, are major causes of morbidity and mortality in patients with types 1 and 2 diabetes. The RAGE extracellular domains are heterogeneous and RAGE ligands may bind at spatially-distinct sites on these domains, thereby indicating that the use of small molecules or antibodies targeted to the extracellular domains, may be ineffective. We have discovered that the interaction of the cytoplasmic tail of RAGE (ctRAGE) with the intracellular formin molecule, DIAPH1, is essential for RAGE-mediated signal transduction. We previously performed a high-throughput screen of >59,000 compounds with the goal to block the interaction of ctRAGE with DIAPH1. We identified two lead series (LS) that fulfill key criteria for drug-like properties; from one of the series, LSII, RAGE229 emerged as a plausible lead for clinical development because of efficacy, favorable pharmacokinetic profile and promising early-stage off-target and toxicity testing. In vivo efficacy was also demonstrated, as administration of RAGE229 attenuated inflammation in a delayed type hypersensitivity experiment in mice, reduced myocardial infarct size upon ligation and reperfusion of the left anterior descending coronary artery in diabetic mice, and reduced multiple parameters of diabetes-associated kidney pathology and impaired wound healing in diabetic mice, all versus vehicle, in both male and female mice. However, in late-stage testing, RAGE229 tested positive in the Mini-AMES test. To address this liability, we have already prepared new analogs of RAGE229; these analogs retain potency but are negative in the Mini-AMES test. In addition, we have made significant progress in developing back-up candidates in the LS I. Importantly, a lead benchmark compound within LSI tested negative in the Mini-AMES test as well. Our established, multi-disciplinary team is now well-poised to move forward aggressively at this critical juncture to identify lead candidate molecules for LSII and the back-up LSI for ultimate clinical development for diabetic complications. Our drug discovery goals, supported by extensive preliminary data are: 1) to identify potent, selective, and safe candidate analogs of LSII; and 2) to develop LSI backup candidates with a different scaffold to mitigate risk to our RAGE program. If successful, our work will set the stage for the development and clinical testing of a novel class of disease-modifying agents for diabetic complications.