Journal: Nature chemical biology

Article Title: Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth

doi: 10.1038/s41589-021-00813-7

Figure Lengend Snippet: a) Representation of binding sites for FKBP12-rapamycin and active-site inhibitors in mTORC1 and mTORC2. Rapamycin has reduced affinity for mTORC2 due to partial occlusion of the FKBP12-rapamycin binding (FRB) domain, while active-site inhibitors have similar affinity for both complexes. b) Schematic representation of components of the bi-steric mTORC inhibitors: the rapamycin core (R), with sites of chemical modification shown as colored marks; the linker, with sites of attachment indicated by geometry of components and green and red color; and the active-site inhibitor analog (ASI). c) Structure of the rapamycin core, showing the linker attachment sites at C40 (green) and C26 (red), and the core modification sites at C32 (pink) and C16 (orange). d) Structures of the bi-steric molecules. The C40-linked bi-steric inhibitor RMC-4627 (BiS-13x) is shown in full, with modifications resulting in the inhibitors RMC-4287 (BiS-NS; replacement of the PP242 active-site inhibitor with MLN0128) and RMC-4745 (Bi-35x; methylcarbamate modification at C16) indicated. The C26-linked bi-steric inhibitor RMC-4529 (BiS-31x) is shown in full, with the C32 (R)-methoxy modification indicated in pink and the C26 oxime linker attachment indicated in red. e) Schematic representation of the design approach combining different linkers, active-site inhibitors, and core modifications to increase selectivity for mTORC1 over mTORC2 while maintaining potency. f) Levels of p4EBP1 T37/T46, pS6K T389, and pAKT S473 determined by MesoScale Discovery (MSD) or AlphaLISA platforms for whole cell lysates from MDA-MB-468 cells incubated with increasing concentrations of indicated compounds for two hours. These are graphs of representative experiments in which each data point is the mean of technical duplicates and normalized to vehicle control, with error bars representing SD. Independent replicate experiments: Rapamycin, n=5; MLN0128, n=7; RMC-4287, n=10; RMC-4627, n=11; RMC-4529, n=5; RMC-4745; n=5.

Article Snippet: mTOR substrate phosphorylation in MDA-MB-468 and MCF-7 cells was assayed using AlphaLISA SureFire Ultra kits for p-4EBP1 Thr37/46, p-P70S6K Thr389, and p-AKT1/2/3 Ser473 (PerkinElmer); and MesoScale Discovery Multi-Array Assay Systems for Phospho-4E-BP1 (Thr37/46) and Phospho-AKT (Ser473) (MSD).

Techniques: Binding Assay, Modification, Incubation

Journal: British Journal of Cancer

Article Title: Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis

doi: 10.1038/sj.bjc.6602442

Figure Lengend Snippet: Genes the expression levels of which differed significantly in the early invasive carcinoma group and the adenoma group (Mann–Whitney U -test)

Article Snippet: Laminin β -3 , D37766 , Cell signalling , 0.7134 , .

Techniques: Expressing

Journal: British Journal of Cancer

Article Title: Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis

doi: 10.1038/sj.bjc.6602442

Figure Lengend Snippet: Genes the expression levels of which differed significantly in the flat-type adenoma group and the protruded-type adenoma group (Mann–Whitney U -test)

Article Snippet: Laminin β -3 , D37766 , Cell signalling , 0.7134 , .

Techniques: Expressing

Journal: British Journal of Cancer

Article Title: Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis

doi: 10.1038/sj.bjc.6602442

Figure Lengend Snippet: Genes the expression levels of which differed significantly in the early invasive carcinoma group and the protruded-type (28 genes) or flat-type (18 genes) adenoma group (Mann-Whitney U -test)

Article Snippet: Laminin β -3 , D37766 , Cell signalling , 0.7134 , .

Techniques: Expressing