Taming the “death receptor”: translating the first-in-class p75NTR modulator LM11A-31 from basic biology, across broad preclinical models, to clinical proof-of-concept

Abstract Background The p75 neurotrophin receptor (p75 NTR ) is a critical regulator of diverse biological processes. Depending on the cellular context, p75 NTR can promote trophic or degenerative signaling, which can influence a broad spectrum of pathological conditions, including neurodegenerative diseases, inflammatory/infectious conditions, and various central and peripheral nervous system injuries. These attributes of p75 NTR and its widespread, frequently upregulated expression on affected cells and tissues, make it a compelling therapeutic target. Among various therapeutic targeting strategies, the first-in-class small molecule p75 NTR modulator, LM11A-31, has emerged as a leading candidate and has been evaluated in 62 published preclinical studies spanning 26 distinct disease and injury models. Main body This review covers the foundational biology of p75 NTR signaling and expression and all published mechanistic and preclinical studies evaluating LM11A-31, focusing on outcomes that have been reproduced across multiple studies and independent labs. Beyond its therapeutic potential, we also explore how LM11A-31 has served as a powerful pharmacological probe, significantly advancing our knowledge of p75 NTR biology. LM11A-31 consistently reduced elevated JNK/c-Jun, NFκB, and RhoA signaling, and normalized reduced PI3K/AKT signaling in a variety of pathological conditions. It also mitigated associated disease processes, including inflammation, degeneration of neurites, synapses, and dendritic spines, and cell death. These protective effects against pathologies often improved functional outcomes, including cognitive and motor measures. Studies using LM11A-31 also uncovered emerging molecular and cellular functions of p75 NTR by demonstrating its ability to improve autophagy, calcium and redox homeostasis, and blood-brain barrier function. Finally, a Phase 2a clinical trial applying LM11A-31 for Alzheimer’s disease demonstrated a favorable safety profile and significantly slowed the progression of biomarkers related to neurodegenerative mechanisms. Conclusions Together, these studies expand our understanding of p75 NTR function and support p75 NTR modulation as a promising therapeutic strategy across diverse pathological conditions.