ChemMedChem

Journal: ChemMedChem

Abbreviation

ChemMedChem

Publisher

Wiley-VCH

ISSN

1860-7179
1860-7187

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Publications 1 - 10 of 23

The Evaluation of l-Tryptophan Derivatives as Inhibitors of the l-Type Amino Acid Transporter LAT1 (SLC7A5)
Graff, Julien; Müller, Jennifer; Sadurni, Anna; et al. (2022)
ChemMedChem
A series of derivatives of the substrate amino acid l-tryptophan have been investigated for inhibition of the L-type amino acid transporter LAT1 (SLC7A5), which is an emerging target in anticancer drug discovery. Of the four isomeric 4-, 5-, 6-, or 7-benzyloxy-l-tryptophans, the 5-substituted derivative was the most potent, with an IC50 of 19 mu M for inhibition of [H-3]-l-leucine uptake into HT-29 human colon carcinoma cells. The replacement of the carboxy group in 5-benzyloxy-l-tryptophan by a bioisosteric tetrazole moiety led to a complete loss in potency. Likewise, the corresponding tetrazolide derived from l-tryptophan itself was found to be neither a substrate nor an inhibitor of the transporter. Increasing the steric bulk at the 5-position, while reasonably well tolerated in some cases, did not result in an improvement in potency. At the same time, none of these derivatives was found to be a substrate for LAT1-mediated transport.
Isolation of a Natural Killer Group 2D Small-Molecule Ligand from DNA-Encoded Chemical Libraries
Dakhel, Sheila; Galbiati, Andrea; Migliorini, Francesca; et al. (2022)
ChemMedChem
Natural Killer Group 2D (NKG2D) is a homo-dimeric transmembrane protein which is typically expressed on the surface of natural killer (NK) cells, natural killer T (NKT) cells, gamma delta T (gamma delta T) cells, activated CD8 positive T-cells and activated macrophages. Bispecific molecules, capable of bridging NKG2D with a target protein expressed on the surface of tumor cells, may be used to redirect the cytotoxic activity of NK-cells towards antigen-positive malignant T-cells. In this work, we report the discovery of a novel NKG2D small molecule binder [K-D=(410 +/- 60) nM], isolated from a DNA-Encoded Chemical Library (DEL). The discovery of small organic NKG2D ligands may facilitate the generation of fully synthetic bispecific adaptors, which may serve as an alternative to bispecific antibody products and which may benefit from better tumor targeting properties.
Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis
Crane, Christine M.; Hirsch, Anna K.H.; Alphey, Magnus S.; et al. (2008)
ChemMedChem
Exploring the flap pocket of the antimalarial target plasmepsin II: The '55 % Rule' Applied to Enzymes
Zürcher, Martina; Gottschalk, Thomas; Meyer, Solange; et al. (2008)
ChemMedChem
Developing Low Molecular Weight PET and SPECT Imaging Agents
Xue, Lian; Jie, Caitlin V.M.L.; Desrayaud, Sandrine; et al. (2024)
ChemMedChem
Imaging agents for positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) have shown their utility in many situations, answering clinical questions related to drug development and medical considerations. The discovery and development of imaging agents follow a well-understood process, with variations related to available starting points and to the envisaged imaging application. This article describes the general development path leading from the expression of an imaging need and project initiation to a clinically usable imaging agent. The definition of the project rationale, the design and optimization of early leads, and the assessment of the imaging potential of an imaging agent candidate are followed by preclinical and clinical development activities that differ from those required for therapeutic agents. These include radiolabeling with a positron emitter and first-in-human clinical studies, to rapidly evaluate the ability of a new imaging agent to address the questions it was designed to answer.
[¹⁸F]NP3-627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System
Whitehead, David M.; Fischer, Christian; Briard, Emmanuelle; et al. (2025)
ChemMedChem
We describe the identification of a candidate positron emission tomography (PET) imaging agent for the NLRP3 protein. NLRP3 plays a critical role in the immune system and has proven a difficult target for the development of imaging agents due to its low and cell-specific expression profile. A recently described series of pyridazine-based inhibitors, with improved permeability and brain-penetration properties, was used as a starting point for the development of a suitable PET imaging agent. Optimization of affinity, non-specific binding and pharmacokinetic properties led to the identification of aminopyridazine (R)-2-(6-((1-cyclopropylpiperidin-3-yl)amino)pyridazin-3-yl)-5-fluoro-3-methylphenol (17 b), which meets the preclinical profile of a successful imaging agent, and whose tritiated version demonstrated excellent specificity in a radioligand saturation binding assay, confirming its imaging potential.18F labeling led to [18F]NP3-627, the proposed PET imaging agent.
Molecules that Changed the World
Altmann, Karl-Heinz (2008)
ChemMedChem
Ligand-based vascular targeting of disease
Rybak, Jascha-N.; Trachsel, Eveline; Scheuermann, Jörg; et al. (2007)
ChemMedChem
Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands
Wünsch B.; Thum, Simone; Schepmann, Dirk; et al. (2018)
ChemMedChem
Designing Anticancer Peptides by Constructive Machine Learning
Grisoni, Francesca; Neuhaus, Claudia S.; Gabernet, Gisela; et al. (2018)
ChemMedChem

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Journal: ChemMedChem

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