The xanthone derivate 5',6'-dimethylxanthenone-4-acetic acid (DMXAA, also known as ASA404 or vadimezan) is a potent agonist of murine STING (stimulator of interferon genes), but cannot activate human STING. Herein we report that α-mangostin, which bears the xanthone skeleton, is an agonist of human STING, but activates murine STING to a lesser extent. Biochemical and cell-based assays indicate that α-mangostin binds to and activates human STING, leading to activation of the downstream interferon regulatory factor (IRF) pathway and production of type I interferons. Furthermore, our studies show that α-mangostin has the potential to repolarize human monocyte-derived M2 macrophages to the M1 phenotype. The agonist effect of α-mangostin in the STING pathway might account for its antitumor and antiviral activities.
The
development of bifunction al molecules, which can
enable targeted
RNA degradation, targeted protein acetylation, or targeted protein
degradation, remains a time-consuming process that requires tedious
optimization. We propose a split-and-mix nanoplatform that serves
as a self-adjustable platform capable of facile screening, programmable
ligand ratios, self-optimized biomolecule spatial recognition, and
multifunctional applications. Herein, we demonstrate the potential
of our proposed nanoplatform by showcasing proteolysis-targeting chimeras
(PROTACs), namely, split-and-mix PROTAC (SM-PROTAC). We highlight
the scope of our platform through the targeted disruption of intracellular
therapeutic targets involving ERα, CDK4/6, AR, MEK1/2, BRD2/4,
BCR-ABL, etc. These studies confirm the effectiveness and universality
of the SM-PROTAC platform for proximity-induced applications. This
platform is programmable, with significant potential applications
to biomolecule regulation, including the fields of epigenetics, gene
editing, and biomolecule modification regulation.
N6-methyladenosine (m6A) is the most abundant internal chemical modification of eukaryotic mRNA and plays diverse roles in gene regulation. The m6A modification plays a significant role in numerous cancer types, including kidney, stomach, lung, bladder tumors, and melanoma, through varied mechanisms. As direct m6A readers, the YT521-B homology domain family proteins (YTHDFs) play a key role in tumor transcription, translation, protein synthesis, tumor stemness, epithelial–mesenchymal transition (EMT), immune escape, and chemotherapy resistance. An in-depth understanding of the molecular mechanism of YTHDFs is expected to provide new strategies for tumor treatment. In this review, we provide a systematic description of YTHDF protein structure and its function in tumor progression.
The diversity of cyclic peptides was expanded by elaborating Mitsunobu macrocyclization, tethering various hydroxy acid building blocks with different N ε -amine substituents. This new strategy was then applied in synthesizing peptidomimetic estrogen receptor modulator (PERM) analogs on the solid support. The PERM analogs exhibited increased serum peptidase stability, cell penetration, and estrogen receptor α binding affinity. Studying diversity-oriented methods for preparing azacyclopeptides provides a new tool for macrocycle construction and further structural information for optimizing ERα modulators for ER positive breast cancers.
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