The goal is to develop novel therapeutics effective in stroke. This will be achieved by advancing candidate molecules toward clinical application utilizing our assay cascade to identify novel, selective inhibitors of the 12/15 lipoxygenase that protect against ischemic stroke. Our drug discovery approach will be to synthesize novel ligands based on the LOXBlock inhibitors that are potent inhibitors of the human 12/15 lipoxygenase and that protect neurons against oxidative stress-related cell death. Candidate molecules will undergo profiling to assess criteria specifically related to the physicochemical properties of compounds in a therapeutic setting, including enzyme selectivity and tests to determine potential interactions with key metabolic enzyme systems. Best candidates will be tested for protection against experimental stroke in mice.
|Maher, Pamela; van Leyen, Klaus; Dey, Partha Narayan et al. (2018) The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium 70:47-55|
|Karatas, H; Eun Jung, Joo; Lo, E H et al. (2018) Inhibiting 12/15-lipoxygenase to treat acute stroke in permanent and tPA induced thrombolysis models. Brain Res 1678:123-128|
|Yigitkanli, Kazim; Zheng, Yi; Pekcec, Anton et al. (2017) Increased 12/15-Lipoxygenase Leads to Widespread Brain Injury Following Global Cerebral Ischemia. Transl Stroke Res 8:194-202|
|Kuhn, Hartmut; Banthiya, Swathi; van Leyen, Klaus (2015) Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta 1851:308-30|
|van Leyen, Klaus; Holman, Theodore R; Maloney, David J (2014) The potential of 12/15-lipoxygenase inhibitors in stroke therapy. Future Med Chem 6:1853-5|