cb 839  (TargetMol)

Journal: Signal Transduction and Targeted Therapy

Article Title: Hyperglutaminolysis drives senescence and aging through arginine-mTORC1 axis activation

doi: 10.1038/s41392-026-02576-w

Figure Lengend Snippet: Hyperglutaminolysis enhances arginine biosynthesis in senescent cells and aged flies. a Venn diagram of metabolites detected by LC-MS/MS-based metabolomics assay ( n = 5 per group). These metabolites are classified into three subsets: the upregulated ones in senescent NIH3T3 cells (green, H vs C UP, p ≤ 0.05, fold change ≥ 1), the downregulated ones in CB-839 (1 μM, 36 hours)-treated senescent cells (red, HCB vs H DOWN, p ≤ 0.05, fold change ≤ 1), and those engaged in the “GLS-related pathway” (blue, GLS-related). 12 metabolites situated in the intersection of these 3 subsets are listed on the right side. b A sketch map of the arginine synthesis pathway linked to glutaminolysis. c – n Levels of metabolites involved in arginine synthesis detected by LC-MS/MS assays and CB-839-caursed alterations (delta levels) of these metabolites, in proliferating (Pro) and senescent (Sen) cells. These metabolites are glutamine (Gln, c , d ), arginine (Arg, e , f ), glutamate (Glu, g , h ), ammonia (NH 4 + , i , j ), aspartate (Asp, k , l ) and citrulline (Cit, m , n ). Levels of arginine, aspartate and citrulline in naturally aged ( o ) and H 2 O 2 -stressed ( p ) flies, with young and unstressed controls. Arginine ( q ) and NH 4 + ( r ) levels in the control and H 2 O 2 -stressed flies treated without or with DON (0.1 μM, 3 days). s Levels of arginine, aspartate and citrulline in wild-type and Gls -KD flies. All metabolite assays used pooled homogenates of at least 20 flies per group and were executed with three technical replicates. Histogram data are shown as mean ± SD. Student’s t-test: * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, n.s . non-significant

Article Snippet: Adriamycin HCl (ADR, S1208), Bafilomycin A1 (BafA1, S1413) were purchased from Selleck (Houston, USA); ammonium chloride (NH 4 Cl) and hydrogen peroxide (H 2 O 2 ) were purchased from CHRON Chemical (Chengdu, China); 6-Diazo-5-oxo-L-nor-leucine (DON, HY-108357) was purchased from MedChemExpress (NJ, USA); CB-839 (Telaglenastat, T6797) was purchased from TargetMol (Massachusetts, USA); L-glutamine (Gln, G8540) was purchased from Merck (Darmstadt, Germany); sodium glutamate hydrate (glutamate, Glu, A602012), L-aspartic acid sodium salt monohydrate (aspartate, Asp, A601178), L-citrulline (Cit, A604057) and L-arginine (Arg, A600205) were purchased from Sangon Biotech (Shanghai, China).

Techniques: Liquid Chromatography with Mass Spectroscopy, Control

Journal: Nature

Article Title: Ageing promotes metastasis via activation of the integrated stress response

doi: 10.1038/s41586-026-10216-0

Figure Lengend Snippet: a , Schematic of [1,2- 13 C]- d -glucose tracing in glycolysis (blue circles) or the pentose phosphate pathway (PPP) (grey circles). b , c , Fractions of labelled pyruvate ( b ) and lactate ( c ) from [1,2- 13 C]- d -glucose in KP -Y and KP -O ( n = 6). d , Schematic of [U 13 C]- l -glutamine tracing (pink circles). e , Mass isotopomer analysis of glutamate (Glu), fumarate (Fum), citrate (Cit) and aspartate (Asp) from [U 13 C]- l -glutamine tracing in KP -Y ( n = 6) and KP -O ( n = 4). f , g , Oxygen consumption rate (OCR) ( f ) and extracellular acidification rate (ECAR) ( g ) in KP -Y ( n = 10) and KP -O ( n = 11). h , i , Mass isotopomer analysis of indicated TCA intermediates from [U 13 C]- l -glutamine tracing in KP -Y, KP -O, KP -Y sh Atf4 .2, KP -O sh Atf4 .2 ( h ) and in KP -Y; KP -Y ATF4 o/e; KP -O and KP -O ATF4 o/e ( i ) ( n = 4 per condition). j , Relative viability of KP -Y and KP -O treated with CB-839 ( n = 3) k , Heatmap of relative viability for KP -Y and KP -O treated with 0.1 μM CB-839 and the indicated compounds. All data points are relative to vehicle (Veh)-treated controls ( n = 3). l , Anoikis resistance of KP -Y; KP -Y ATF4 o/e; KP -O and KP -O ATF4 o/e treated with 0.1 μM CB-839 for 48 h ( n = 3). m , Heatmap of anoikis resistance of KP -Y and KP -O treated with 0.1 μM CB-839 and the indicated compounds. All data points are relative to vehicle-treated controls ( n = 3). n , o , Lung metastasis burden measured by means of bioluminescence ( n ) or H&E quantification ( o ) (with representative images) in mice after intravenous injections of KP -Y and KP -O and treated with CB-839 or vehicle ( n = 4, 3, 4, 5). p , q , Longitudinal tumour growth of subcutaneous tumours ( KP -Y n = 24, KP -Y + CB-839 n = 22, KP -O n = 26 and KP -O + CB-839 n = 18 tumours) ( p ) and H&E quantification of lung metastases foci ( n = 12, 11, 13 and 9 mice, respectively) ( q ). Mice were administered CB-839 once the tumours reached 100 mm 3 in size. Data are mean ± s.e.m. Two-sided multiple unpaired t -tests ( b , c , e – i , q ), two-way ANOVA ( j , p ), one-way ANOVA with Tukey’s multiple comparisons test ( l , n , o ). 5ME-THF, 5-methyltetrahydrofolate; NAC, N -acetyl- l -cysteine; NEAA, non-essential amino acids; NS, not significant. Scale bars, 1 mm.

Article Snippet: For CB-839 studies, mice were randomized and subjected to treatment with either 200 mg kg −1 body weight CB-839 (no. HY-12248, MedChemExpress) or vehicle.

Techniques:

Journal: Nature

Article Title: Ageing promotes metastasis via activation of the integrated stress response

doi: 10.1038/s41586-026-10216-0

Figure Lengend Snippet: a , Cell viability measured by CellTiter-Glo of KP -Y and KP -O primary cultures treated for 72 h with 1 µM ISRIB followed by 0.1 µM CB-839 treatment for another 72 h. All values were normalized to their respective vehicle-treated control ( n = 3). b , Cell viability measured by CellTiter-Glo of KP -Y and KP -O (sg Tom or sg Atf4) treated with 0.0625 µM CB-839 for 72 h. All values were normalized to their respective vehicle-treated control ( n = 3). c , Relative viability assessed by CellTiter-Glo of KP- Y and KP -O expressing either control or ATF4 o/e following 0.1 µM CB-839 treatment for 72 h. All values were normalized to their respective vehicle-treated control ( n = 3). d , Anoikis resistance of KP -Y and KP -O treated with either vehicle control, 0.1 µM CB-839, 5 µM BPTES or 2 µM V9302 ( n = 6). e , Anoikis resistance of KP -Y and KP -O treated twice a day for 72 h with 2 μM ISRIB and then seeded in ULA plates with either vehicle, 0.1 µM CB-839, 2 µM ISRIB or a combination of both ( n = 3). f , Correlation analysis between ATF4 expression and CB-839 sensitivity in human lung adenocarcinoma (LUAD) cell lines ( n = 45) from Dependency Map (DepMap) portal. Primary tumor cell lines are depicted with grey squares, metastatic cell lines with pink circles. g-i , KP -Y and KP -O subcutaneously injected in mice. Mice were administered 200 mg/kg CB-839 p.o twice/day every other day for the duration of the experiment once the tumors reached 100 mm 3 in size. Complementary results presented in Fig. and Fig. . g , Endpoint tumor weight after subcutaneous injections of KP -Y and KP -O. h , Lung metastasis burden. i , Left, H&E- stained lung sections showing metastatic foci in the lungs (black and red arrows). Right, close-up of the area identified by the red arrow in the left panel (Scale bars, 1 mm and 100 µm). Data are mean values ± s.e.m. Ordinary one-way ANOVA with Tukey’s multiple comparisons test (a,b,d,e,g,h ), two-way ANOVA ( c ) and simple linear regression ( f ).

Article Snippet: For CB-839 studies, mice were randomized and subjected to treatment with either 200 mg kg −1 body weight CB-839 (no. HY-12248, MedChemExpress) or vehicle.

Techniques: Control, Expressing, Injection, Staining