3 research outputs found
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