Author: Xie, Ling ; Qian, Chao ; Guccione, Ernesto ; Xiong, Yan ; Chen, Xian ; Shen, Yudao ; Jin, Jian ; Chen, Matthew ; Hu, Jacqueline ; Kim, Huensuk ; Zhong, Yue

Protein arginine methyltransferase 5 (PRMT5) plays crucial roles in the regulation of various biological processes through the mono- and symmetric dimethylation of protein substrates. PRMT5 is overexpressed in various human cancers and its overexpression is associated with poor prognosis. We previously reported the first-in-class PRMT5 degrader, MS4322, which is also the only von Hippel-Lindau (VHL)-recruiting PRMT5 degrader to date. Here, we performed structure-activity relationship (SAR) studies exploring various linkers and ligands of VHL and PRMT5, which resulted in the best-in-class PRMT5 degrader, MS115 (compound 10). Compound 10 potently and selectively degraded PRMT5 and its coactivator, MEP50, in concentration-, time-, and ubiquitin-proteasome system-dependent manners. It displayed much improved PRMT5/MEP50 degradation potency over MS4322, which translated to better antiproliferative effect in both breast and prostate cancer cells. Overall, we discovered a highly potent and selective PRMT5/MEP50 complex degrader, which is an invaluable chemical biology tool and a potential cancer therapeutic.

PLOS ONEQ3 · CROSS-FIELD

Identification of endogenous normalizing genes for expression studies in inguinal ring tissue for scrotal hernias in pigs

Q3 · CROSS-FIELD

ArticleOA

Author: Lorenzetti, William Raphael ; Peixoto, Jane de Oliveira ; Savoldi, Igor Ricardo ; Ledur, Mônica Corrêa ; Oliveira, Haniel Cedraz de ; Ibelli, Adriana Mercia Guaratini ; Carmo, Kamilla Bleil do ; Mores, Marcos Antonio Zanella

The use of reference genes is required for relative quantification in gene expression analysis and since the stability of these genes could be variable depending on the experimental design, it has become indispensable to test the reliability of endogenous genes. Therefore, this study evaluated 10 reference candidate genes in two different experimental conditions in order to obtain stable genes to be used as reference in expression studies related to scrotal hernias in pigs. Two independent experiments were performed: one with 30 days-old MS115 pigs and the other with 60 days-old Landrace pigs. The inguinal ring/canal was collected, frozen and further submitted to real-time PCR analysis (qPCR). For the reference genes stability evaluation, four tools were used: GeNorm in the SLqPCR, BestKeeper, NormFinder and Comparative CT. A general ranking was generated using the BruteAggreg function of R environment. In this study, the RPL19 was one of the most reliable endogenous genes for both experiments. The breed/age effects influenced the expression stability of candidate reference genes evaluated in the inguinal ring of pigs. Therefore, this study reinforces the importance of evaluating the stability of several endogenous genes previous their use, since a consensual set of reference genes is not easily obtained. Here, two sets of genes are recommended: RPL19, RPL32 and H3F3A for 30-days MS115 and PPIA and RPL19 for the 60 days-old Landrace pigs. This is the first study using the inguinal ring tissue and the results can be useful as an indicative for other studies working with gene expression in this tissue.

MoleculesQ3 · CHEMISTRY

Novel 5′-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents

Q3 · CHEMISTRY

ArticleOA

Author: Solyev, Pavel N ; Leonova, Olga G ; Seley-Radtke, Katherine L ; Andreevskaya, Sofya N ; Buckheit, Karen W ; Chernousova, Larisa N ; Wilkinson, Maggie ; Khandazhinskaya, Anastasia L ; Popenko, Vladimir I ; Efremenkova, Olga V ; Kochetkov, Sergey N ; Smirnova, Tatiana G ; Buckheit, Robert W ; Matyugina, Elena S ; Alexandrova, Liudmila A

A series of novel 5′-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC99 of 67 μg/mL (mc2155) and a MIC99 of 6.7–67 μg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC99 28–61 μg/mL) and Mycobacterium bovis ATCC 35737 (MIC99 50–60 μg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC99 20–50 μg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC99 20–50 μg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	United States	UNC Systems AB	15 Apr 2025
Breast Cancer	Preclinical	United States	Icahn School of Medicine at Mount Sinai	15 Apr 2025
Prostatic Cancer	Preclinical	United States	Icahn School of Medicine at Mount Sinai	15 Apr 2025
Prostatic Cancer	Preclinical	United States	UNC Systems AB	15 Apr 2025

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