Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint

Konieczny, Magdalena; Musielak, Bogdan; Kocik, Justyna; Skalniak, Łukasz; Sala, Dominik; Czub, Miroslawa; Magiera‐Mularz, Katarzyna; Rodríguez, Ismael; Myrcha, Maja; Stec, Małgorzata; Siedlar, Maciej; Holak, Tad A.; Plewka, Jacek

doi:10.1021/acs.jmedchem.0c01260

Cited by 60 publications

(73 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to their size and instability, antibodies need to be administered by injection and cannot pass the blood brain barrier. Of note, small molecules that disrupt PD-1/PD-L1 interaction are currently in development ( 84 , 85 ).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO

Kim

Tomek

2021

Front. Immunol.

View full text Add to dashboard Cite

Blockade of the immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) holds enormous promise for sensitising cancer patients to immune checkpoint blockade. Yet, only IDO1 inhibitors had entered clinical trials so far, and those agents have generated disappointing clinical results. Improved understanding of molecular mechanisms involved in the immune-regulatory function of the tryptophan catabolism is likely to optimise therapeutic strategies to block this pathway. The immunosuppressive role of tryptophan metabolite kynurenine is becoming increasingly clear, but it remains a mystery if tryptophan exerts functions beyond serving as a precursor for kynurenine. Here we hypothesise that tryptophan acts as a rheostat of kynurenine-mediated immunosuppression by competing with kynurenine for entry into immune T-cells through the amino acid transporter called System L. This hypothesis stems from the observations that elevated tryptophan levels in TDO-knockout mice relieve immunosuppression instigated by IDO1, and that the vacancy of System L transporter modulates kynurenine entry into CD4+ T-cells. This hypothesis has two potential therapeutic implications. Firstly, potent TDO inhibitors are expected to indirectly inhibit IDO1 hence development of TDO-selective inhibitors appears advantageous compared to IDO1-selective and dual IDO1/TDO inhibitors. Secondly, oral supplementation with System L substrates such as leucine represents a novel potential therapeutic modality to restrain the immunosuppressive kynurenine and restore anti-tumour immunity.

show abstract

Section: Discussionmentioning

confidence: 99%

Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO

Kim

Tomek

2021

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…For instance, small molecule inhibitors can be incubated in a co-culture system with T cells expressing PD-1 and APCs/tumor cells expressing PD-L1. The blocking abilities of small molecule inhibitors can be evaluated by measuring PD-1/PD-L1 expression using flow cytometry [ 104 ]. Similarly, in a single-type cell incubated with PD-1 or PD-L1 protein, the blocking affinity of small molecule inhibitors against PD-1 or PD-L1 protein is measured by the qualification of fluorescence intensity.…”

Section: Current Methodologies For the Development Of Pd-1/pd-l1 Inhibitorsmentioning

confidence: 99%

“…Over the past decade, with a more advanced understanding of PD-1/PD-L1 interactions and the underlying mechanisms, there has been an explosion of interest in the development of bioassays that can be applied for screening small molecule inhibitors against PD-1/PD-L1 [ 64 , 88 , 101 , 102 , 104 ]. Biophysical and biochemical assays are powerful for screening the promising "hits" and for characterizing the binding parameters between identified "hits" and PD-1/PD-L1.…”

Section: Perspectivementioning

confidence: 99%

Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

Liu

Seeram

2021

Cancer Cell Int

View full text Add to dashboard Cite

Programmed death-1/programmed death ligand-1 (PD-1/PD-L1) based immunotherapy is a revolutionary cancer therapy with great clinical success. The majority of clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies but their applications are limited due to their poor oral bioavailability and immune-related adverse effects (irAEs). In contrast, several small molecule inhibitors against PD-1/PD-L1 immune checkpoints show promising blockage effects on PD-1/PD-L1 interactions without irAEs. However, proper analytical methods and bioassays are required to effectively screen small molecule derived PD-1/PD-L1 inhibitors. Herein, we summarize the biophysical and biochemical assays currently employed for the measurements of binding capacities, molecular interactions, and blocking effects of small molecule inhibitors on PD-1/PD-L1. In addition, the discovery of natural products based PD-1/PD-L1 antagonists utilizing these screening assays are reviewed. Potential pitfalls for obtaining false leading compounds as PD-1/PD-L1 inhibitors by using certain binding bioassays are also discussed in this review.

show abstract

“…2 µM) [5,18,22]. Some other molecules were shown to be less toxic, with 50% cell growth inhibition values above 10-30 µM [12,19,20].…”

Section: The Comparison Of In Vitro Activitiesmentioning

confidence: 99%

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

Surmiak

Magiera‐Mularz

Musielak

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

show abstract

Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint

Cited by 60 publications

References 37 publications

Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO

Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO

Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

Contact Info

Product

Resources

About