DDL-357

DDL-357 is a small molecule secreted clusterin (sCLU) enhancer identified as a brain-permeable BET (bromodomain and extra-terminal domain) inhibitor[1][2][3][9]. It increases levels of sCLU, a protein that protects against amyloid-beta and tau buildup, both central to Alzheimer's disease pathology[1][3][4][7][9]. DDL-357 has shown neuroprotective effects in Alzheimer’s disease mouse models, including increased sCLU and SirT1 expression, upregulation of humanin, and promotion of neurite outgrowth[1][2]. In vivo, DDL-357 reduced phospho-tau levels, improved mitochondrial function, and restored cognitive performance in Alzheimer’s disease models[1][2][3][4][7]. No overt toxicity was observed at concentrations much higher than used therapeutically[2]. Its EC50 for sCLU increase is 223 nM[2][9][10]. DDL-357 is still in preclinical development, studied mainly at UCLA Health and associated research groups[1][3][4][7].