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Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models.
J Med Chem
January 2025
Medicinal Chemistry Department, Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Pudong New Area, Shanghai 201203, China.
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of -methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design.
View Article and Find Full Text PDFSalvicsite A-C: Three Seco-Norabietane Diterpenoids Including an Unusual Tetracyclic Skeleton from Diels f. Stib.
J Org Chem
January 2025
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Three seco-norabietane diterpenoids, salvicsites A-C (-), along with two known compounds, were isolated from the roots and rhizomes of Diels f. Stib. Salvicsite A () represents an unprecedented structural combination, featuring an eight-membered α-methyl-α,β-unsaturated lactone ring and a five-membered α,β-unsaturated lactone ring, based on a 6/6/5/8 ring system.
View Article and Find Full Text PDFTissue-specific roles of de novo DNA methyltransferases.
Epigenetics Chromatin
January 2025
Department of Molecular Biology, Semmelweis University, Budapest, Hungary.
DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in regulating embryonic development, gene expression, adaption to environmental stress, and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and the enzymatically inactive DNMT3L. DNMT3A and DNMT3B establish novel methylation patterns maintained by DNMT1 during replication.
View Article and Find Full Text PDFExercise intensity and training alter the innate immune cell type and chromosomal origins of circulating cell-free DNA in humans.
Proc Natl Acad Sci U S A
January 2025
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
Exercising regularly promotes health, but these benefits are complicated by acute inflammation induced by exercise. A potential source of inflammation is cell-free DNA (cfDNA), yet the cellular origins, molecular causes, and immune system interactions of exercise-induced cfDNA are unclear. To study these, 10 healthy individuals were randomized to a 12-wk exercise program of either high-intensity tactical training (HITT) or traditional moderate-intensity training (TRAD).
View Article and Find Full Text PDFThe microbiota of cork and yellow stain as a model for a new route for the synthesis of chlorophenols and chloroanisoles from the microbial degradation of suberin and/or lignin.
Microbiome
January 2025
Instituto de Investigación de La Viña y El Vino, Escuela de Ingeniería Agraria, Universidad de León, Avenida de Portugal, 41, León, 24009, Spain.
Article Synopsis
- Cork is primarily used for wine bottle stoppers, but it can contain 2,4,6-trichloroanisole, which causes a musty odor that negatively affects wine quality and leads to financial losses.
- The presence of yellow stain in cork indicates a degradation linked to higher microbial populations, particularly filamentous fungi that break down lignin, and this microbiota contributes to the formation of chlorophenols and chloroanisoles.
- Research identified specific fungal and bacterial species associated with yellow stain and demonstrated that certain strains can convert p-hydroxybenzoate into phenol, which can then be chlorinated, potentially leading to the development of 2,4,6-trichlorophenol.
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