Journal: Genome Medicine

Article Title: The expressed mutational landscape of microsatellite stable colorectal cancers

doi: 10.1186/s13073-021-00955-2

Figure Lengend Snippet: Correlation between TP53 and RAS / BRAF V600E mutation expression levels and sensitivity to targeted anticancer agents in pre-clinical models. a Sensitivity to the EGFR inhibitor erlotinib, the MEK inhibitor trametinib, and the MDM2 inhibitor idasanutlin in a panel of 29 unique CRC cell lines plotted according to RAS / BRAF V600E or TP53 mutation status, as indicated (mut, mutated; wt, wild-type; color codes are shown in c ). Higher DSS indicates stronger sensitivity. p -value is from Welch’s t -test of wild-type versus mutated samples. b , c Upper panels show the mutation status for RAS / BRAF V600E and TP53 in each of the 7 selected cell lines and 8 patient-derived organoids (PDOs). Scatter plots show the DSS of matched drugs versus mutant allele expression levels (color-coded as indicated). Spearman’s correlations in blue are for KRAS -mutated PDOs only (excluding the single NRAS -mutated sample). d Scatter plot of RNA-level versus DNA-level MAFs of RAS and TP53 in matched primary and metastatic tumor samples from each of four patients (three with RAS mutations and two with TP53 mutations). Patient 2 showed higher relative expression of the RAS mutant allele in the metastasis

Article Snippet: The MDM2-TP53 inhibitor idasanutlin (MedChemExpress, Monmouth Junction, NJ, USA), three EGFR inhibitors (afatinib: Selleck Chemicals; erlotinib: MedChemExpress; and lapatinib: LC Laboratories, Woburn, MA, USA) and two MEK inhibitors (binimetinib and trametinib, ChemieTek, Indianapolis, IN, USA) were included in the screens at five and nine different concentrations over a 10,000-fold concentration range each (typically 1–10,000 nmol/L) in the cell lines and PDOs, respectively.

Techniques: Mutagenesis, Expressing, Derivative Assay

Journal: Journal of medicinal chemistry

Article Title: Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer

doi: 10.1021/acs.jmedchem.3c00917

Figure Lengend Snippet: Examples of reported inhibitors of m7GpppX cap binding to eIF4E and proposed acyclic nucleoside phosphonate prodrugs inspired by the anti-viral drugs, adefovir and tenofovir dipivoxil.

Article Snippet: These compounds, in addition to recently reported small molecule eIF4E inhibitors reported by eFFECTOR Therapeutics, 40 will provide important tools for validating eIF4E as an anti-cancer therapeutic target, as well as provide new insights into the role of cap-dependent translation in cancer and other relevant human diseases.

Techniques: Binding Assay

Journal: Journal of medicinal chemistry

Article Title: Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer

doi: 10.1021/acs.jmedchem.3c00917

Figure Lengend Snippet: eIF4E bound to 7n. The eIF4E protein backbone is shown as a gray ribbon with residues that interact with 7n shown as sticks. 7n is shown as sticks with cyan carbons. Nitrogen atoms are colored blue, oxygens in red and phosphorus in orange. Dashed lines represent hydrogen bonds (PDB: 8SX4).

Article Snippet: These compounds, in addition to recently reported small molecule eIF4E inhibitors reported by eFFECTOR Therapeutics, 40 will provide important tools for validating eIF4E as an anti-cancer therapeutic target, as well as provide new insights into the role of cap-dependent translation in cancer and other relevant human diseases.

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer

doi: 10.1021/acs.jmedchem.3c00917

Figure Lengend Snippet: Activation of eIF4E and cap-dependent translation.

Article Snippet: These compounds, in addition to recently reported small molecule eIF4E inhibitors reported by eFFECTOR Therapeutics, 40 will provide important tools for validating eIF4E as an anti-cancer therapeutic target, as well as provide new insights into the role of cap-dependent translation in cancer and other relevant human diseases.

Techniques: Activation Assay