3 research outputs found
An Fc Domain Protein–Small Molecule Conjugate as an Enhanced Immunomodulator
Proteins as well as small molecules
have demonstrated success as
therapeutic agents, but their pharmacologic properties sometimes fall
short against particular drug targets. Although the adenosine 2a receptor
(A<sub>2A</sub>R) has been identified as a promising target for immunotherapy,
small molecule A<sub>2A</sub>R agonists have suffered from short pharmacokinetic
half-lives and the potential for toxicity by modulating nonimmune
pathways. To overcome these limitations, we have tethered the A<sub>2A</sub>R agonist CGS-21680 to the immunoglobulin Fc domain using
expressed protein ligation with Sf9 cell secreted protein. The protein
small molecule conjugate Fc-CGS retained potent Fc receptor and A<sub>2A</sub>R interactions and showed superior properties as a therapeutic
for the treatment of a mouse model of autoimmune pneumonitis. This
approach may provide a general strategy for optimizing small molecule
therapeutics
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