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Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking\/immunoprecipitation assay. Further evaluation of two compounds (Cpd\u00a0A and Cpd\u00a0G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. 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They stand to gain royalties from their future commercialization. A.F. is Chief Scientific Officer of L&F Health LLC, holds equity interests in L&F Research and is the inventor of assets developed by ZyVersa Therapeutics. ZyVersa has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for treatment of kidney disease from L&F Research. A.F. holds equity in River 3 Renal Corporation. S.M. is a consultant for Kintai Therapeutics, Inc and holds equity interest in L&F Research. A.F. and S.M. are supported by Hoffman-La Roche and by Boehringer Ingelheim. M.P., M.W., C.K., C.M., JP.C., and S.R. were employees of Hoffmann-La Roche Ltd at the time of those experiments. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4662"}}