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

Journal: Scientific Reports

Article Title: Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site

doi: 10.1038/s41598-022-18760-1

Figure Lengend Snippet: IL17A binding sites and discovery of novel binding site by NMR based fragment screening. ( A ) Overlay of apo IL17A (tan ribbon) with complexed IL17A structure (green ribbon; PDB 5HI3) with Pfizer macrocycle (Cmpd 2; light blue: Pfizer macrocycle) and Pfizer linear peptide (Cmpd 3; red). ( B ) IL17A complexed with IL17 Receptor A (PDB 4HSA). ( C , D ) 13 C-HSQC spectra (recorded at 600 MHz) of IL17A isotopically labeled at the methyl groups of isoleucine (δ), valine, leucine and methionine. ( C ) Overlay of spectra recorded in the absence (black) and presence (red) of Pfizer macrocycle (Cmpd 2). ( D ) Overlay of spectra recorded in the absence (black) and presence (red) of Cmpd 4. In each case, blue arrows highlight observed perturbations upon compound binding. ( E ) Ribbon structure of IL-7A dimer showing Met46 and Met110 as sticks or spheres. ( F ) “End view” of IL17A C-terminus showing potential pocket for fragment binding.

Article Snippet: When we initially undertook our studies aimed at discovering a small-molecule inhibitor of IL17A signaling, the only known, small-molecule, inhibitor was that from Ensemble Therapeutics (Cmpd 1; Fig. ).

Techniques: Binding Assay, Labeling

Journal: Scientific Reports

Article Title: Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site

doi: 10.1038/s41598-022-18760-1

Figure Lengend Snippet: ( A ) Structures of Cmpd 6 and ( B ) Cmpd 5 bound to IL17A C-terminal site and highlighted interactions. ( C,D ) Evidence of C-terminal importance was seen in these crystal structures with respect to positioning of His152 ( C ) “Extended position” of His152 in IL17A complex with Cmpd 6 ( D ) Overlay of Cmpd 5 (light orange structure with movement toward His152). In both ( C , D ) the position of the reported IL17 receptor A as bound to IL17A (PDB code 4HSA) is shown as light blue ribbon/surface.

Article Snippet: When we initially undertook our studies aimed at discovering a small-molecule inhibitor of IL17A signaling, the only known, small-molecule, inhibitor was that from Ensemble Therapeutics (Cmpd 1; Fig. ).

Techniques:

Journal: Scientific Reports

Article Title: Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site

doi: 10.1038/s41598-022-18760-1

Figure Lengend Snippet: ( A ) Salicylate fragment Cmpd 7 bound to IL17A. ( B ) Structure of Cmpd 10 and highlighted interaction with His109 residues in each IL17A subunit.

Article Snippet: When we initially undertook our studies aimed at discovering a small-molecule inhibitor of IL17A signaling, the only known, small-molecule, inhibitor was that from Ensemble Therapeutics (Cmpd 1; Fig. ).

Techniques:

Journal: Scientific Reports

Article Title: Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site

doi: 10.1038/s41598-022-18760-1

Figure Lengend Snippet: Biochemical and cellular data for IL17A inhibitors ( A ) Biochemical interaction assay ( B ) FP probe for C-terminal site occupancy: (left) titration of fluoroprobe, Cmpd 11; (middle) competition assay with unlabeled inhibitors and (right) structure of Cmpd 11 ( C ) Cellular inhibition of IL17 signaling. Error bars shown in ( A , C ) reflect the standard error of the mean.

Article Snippet: When we initially undertook our studies aimed at discovering a small-molecule inhibitor of IL17A signaling, the only known, small-molecule, inhibitor was that from Ensemble Therapeutics (Cmpd 1; Fig. ).

Techniques: Titration, Competitive Binding Assay, Inhibition

Journal: Scientific Reports

Article Title: Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site

doi: 10.1038/s41598-022-18760-1

Figure Lengend Snippet: X-ray data and structure refinement statistics.

Article Snippet: When we initially undertook our studies aimed at discovering a small-molecule inhibitor of IL17A signaling, the only known, small-molecule, inhibitor was that from Ensemble Therapeutics (Cmpd 1; Fig. ).

Techniques: