Taming the "death receptor": translating the first-in-class p75^NTR modulator LM11A-31 from basic biology, across broad preclinical models, to clinical proof-of-concept

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 m

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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