Reproducibility Study on a PBPK Model of FcRn-Mediated Recycling for Large Molecules

The PBPK model of FcRn-mediated recycling of large molecules was developed and studied by \cite{de2023mechanistic} to characterize and predict Immunoglobulin G (IgG) disposition in plasma and tissues. This study investigated the large-molecule model in PK-Sim and its applicability to molecules with FcRn binding affinity in plasma. Subsequently, the model was extended to ensure a more mechanistic description of the internalization of FcRn and the FcRn-drug complex. This PBPK model has applications in autoimmune disorders such as primary immune thrombocytopenia which is mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Currently, there are several FcRn inhibitors in clinical development for numerous indications that can benefit from this model. We created a modular implementation of the model in MoBi, which is able to reproduce the originally published data. This Physiome paper describes how to access, run, and manipulate this model, how to parameterize the model to match data, and how to compare model predictions to data. In addition, some inconsistencies have been revealed and discussed in this paper. EDITOR'S NOTE v2: adding OMEX archive. v3: correcting file names. v4: updating publication date

A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor <i>in vitro</i> and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1–/– cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease

A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor <i>in vitro</i> and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1–/– cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease