PU.1 inhibitor A11 is a small molecule inhibitor of transcription factor PU.1 with EC50 of 2.5 nM in reporter assays, moderates the inflammatory response in human iPSC-derived microglia-like cells (iMGLs) by downregulating inflammatory PU.1-target gene expression without affecting hematopoiesis.
A11 is a potent inhibitor of Zymosan A bioparticle and myelin uptake in iMGLs (EC50 < 35 nM), moderates microglial activation in iMGLs.
A11 reduces PU.1-dependent expression by enabling MECP2-dependent repression at PU.1 motifs.
A11 reduces neuropathology and improves cognitive performance in mouse models of Alzheimer's disease (AD)-related neurodegeneration, tauopathy, and β-amyloid deposition, without affecting peripheral hematopoiesis or causing other side effects.
A11 stimulates the recruitment of MECP2, HDAC1, and other co-repressor molecules to PU.1 target genes, such as IL1B and CD14, without affecting PU.1 expression levels.
A11 represents a first-in-class molecule of drugs that converts PU.1 from a transcriptional activator to a transcriptional repressor, resulting in a controlled state of microglial inflammation.