Powell, Jonathan published the artcileSmall Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells, Computed Properties of 39546-32-2, the publication is Journal of Medicinal Chemistry (2018), 61(9), 4135-4154, database is CAplus and MEDLINE.
We report the design, synthesis and comprehensive biol. evaluation of a range of some potent small-mol. neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229 which was used a starting point for optimization. Through targeting of specific amino-acid residues addnl. H-bonding interactions were introduced, which led to increases in binding affinity and potency. The design of these mols. was informed and supported by X-ray crystal structures. Pharmacokinetic data was obtained for some of the most potent compounds, and compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays, and was shown to have anti-angiogenic, anti-migratory and anti-tumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, CD25+ populations of Tregs from mice 1 was able to block a glioma conditioned medium induced increase in TGFβ production This study therefore represents a comprehensive characterization of a small-mol. NRP1 antagonist, and provides the basis for future in vivo studies.
Journal of Medicinal Chemistry published new progress about 39546-32-2. 39546-32-2 belongs to piperidines, auxiliary class Piperidine,Amine,Amide, name is Piperidine-4-carboxamide, and the molecular formula is C6H12N2O, Computed Properties of 39546-32-2.
Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem