Discovery of Novel Small-Molecule Inhibitors of PD-1/PD-L1 Interaction via Structural Simplification Strategy.

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

Corrigendum to "Fluoxetine combined with risperidone in treatment of online gambling disorder-case report" [Heliyon 9 (3) (March 2023) Article e13772].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e13772.].

Fluoxetine combined with risperidone in treatment of online gambling disorder-case report.

Pathological gambling leaves seriously negative impacts on individuals, families, and society. With the universal use of internet, online gambling disorder is also increasing worldwide. However, there is currently a lack of effective treatments, especially medical treatments, for online gambling disorder. This study shared 3 cases of online gambling disorder that was treated with combined fluoxetine and risperidone to provide an option for the treatment of online gambling.

Aminofluorosulfonylation of ß,γ-Unsaturated Hydrazones with Sulfur Dioxide and N-Fluorobenzenesulfonimide: Accessing Pyrazoline-Functionalized Aliphatic Sulfonyl Fluorides.

An efficient aminofluorosulfonylation strategy was developed for the synthesis of various pyrazoline-functionalized aliphatic sulfonyl fluorides using ß,γ-unsaturated hydrazones with sulfur dioxide and NFSI as the starting materials under mild conditions. The sulfonyl fluoride products could be successfully transformed into the corresponding sulfonate esters and amides via the sulfur(VI) fluoride exchange (SuFEx) click reactions. Preliminary mechanistic investigations demonstrate that the reaction operates through a radical cyclization/SO2 insertion/fluorination cascade process.

Photocatalytic C-C Bond Cleavage and Fluorosulfonylation of Strained Cycloalkanols for Carbonyl-Containing Aliphatic Sulfonyl Fluorides.

In this report, we present a photocatalytic ring-opening fluorosulfonylation of strained cycloalkanols with sulfur dioxide and NFSI under mild conditions for the synthesis of carbonyl-containing aliphatic sulfonyl fluorides. The synthetic potential of the carbonyl-containing aliphatic sulfonyl fluoride products has been examined by diverse transformations, including SuFEx reactions and Baeyer-Villiger oxidation reactions. Mechanistic studies demonstrate that the reaction operates through a radical C-C bond cleavage/SO2 insertion/fluorination cascade process.

Metabolomic analysis revealed glycylglycine accumulation in astrocytes after methionine enkephalin administration exhibiting neuron protective effects.

Owing to its unrevealed etiology, multiple sclerosis lacks specific therapies up to now. Experiential administration of methionine enkephalin (MENK) on mouse model improved disease manifestations to some extent. In order to gain more insight on the significance of MENK application, a capillary electrophoresis-mass spectrometry (CE-MS) technique was employed to profile intracellular metabolite fluctuation in 5 astrocytoma cell lines challenged by MENK. The processed data were first evaluated through a bioinformatic process to ensure their compatibility with the study aims and then subjected to multivariate analysis. The results indicated that MENK administration increased intracellular tyrosine, phenylalanine, methionine and glycylglycine. Exemplified by U87 cells, glycylglycine inhibited cell proliferation as well as MENK but it also decreased cell nitric oxide excretion which could not be evoked by MENK. The neuron protective effects were also mirrored by the increased expression of some genes related to remyelination. This study demonstrated CE-MS to be a promising tool for cell metabolomic analysis and benefited the therapeutic exploring of multiple sclerosis with respect to metabolism intervention.