Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3)

Rietz, Tyson A.; Teuscher, Kevin B.; Mills, Jonathan J.; Gogliotti, Rocco D.; Lepovitz, Lance T; Scaggs, W Rush; Yoshida, Koshi; Luong, Kelvin; Lee, Min Ho; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.1c01336

Cited by 19 publications

(25 citation statements)

References 44 publications

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“…However, there are no table entries for papers targeting proteases, the first time this target class has not been represented. In contrast, there are more examples of GPCR case studies in Table than in previous years (entries 26, 27, and 28), including the description of the discovery of the M1 agonist clinical compound HTL9936 (entry 28). …”

Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh¹,

Erlanson²,

Esch

et al. 2023

J. Med. Chem.

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This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in a given year. A tabulated summary of relevant articles published in 2021 is provided, and features such as target class, screening methods, and ligand efficiency are discussed, both for the 2021 examples and for the combined examples over the years 2015−2021. In addition, trends and new developments in the field are summarized. In particular, the use of structural information in fragment-based drug discovery is discussed.

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Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh¹,

Erlanson²,

Esch

et al. 2023

J. Med. Chem.

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“…Recently, the lock has been released. Rietz and coworkers have demonstrated that it is possible to directly target TIM-3 with specifically designed small heterocyclic molecules presenting nanomolar affinities of the receptor [ 95 ]. Alternatively, the TIM-3 checkpoint can be regulated with molecules that binds to the Gal-9 ligand, such as the disaccharide lactose.…”

Section: Discussionmentioning

confidence: 99%

“…Third and more interestingly, small molecule fragments capable of interacting with TIM-3 have been recently identified through an NMR-based fragment screen and optimized. Starting from low-affinity fragments such as the tricyclic triazoloquinazolinone unit (K D = 810 µM), the authors designed and synthesized high-affinity TIM-3 small-molecule ligands, such as compound the sulfonamide derivative 35 ( Figure 4 ) with a strongly reinforced affinity for TIM-3 (K i = 156 nM) [ 95 ]. This is a clever and promising approach toward the discovery of TIM-3-targeted therapeutics, even if at present the anticancer potential of these molecules has not been reported.…”

Section: Small Molecules Targeting Tim-3/gal-9 Checkpointmentioning

confidence: 99%

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Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Bailly

Thuru

Quesnel

2021

Cancers

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The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

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“…NMR spectroscopy is widely used in studies of structure–activity relationships (SAR) of potential lead compounds − and in fragment-based drug discovery (FBDD). − 19 F-probes are attractive because of the wide chemical shift range of 19 F-NMR, the high sensitivity of 19 F for NMR detection, and the absence of background 19 F-NMR signals in natural biological samples. In the limiting situation where exchange between bound and free ligand is slow on the chemical shift time scale, displacement of the probe molecule from its binding site can be measured by the decrease of the NMR signal intensity for the bound state (Figure S1).…”

mentioning

confidence: 99%

Adenosine A_2A Receptor (A_2AAR) Ligand Screening Using the ¹⁹F-NMR Probe FPPA

et al. 2023

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The binding affinity of G protein-coupled receptor (GPCR) ligands is customarily measured by radio-ligand competition experiments. As an alternative approach, 19 F nuclear magnetic resonance spectroscopy ( 19 F-NMR) is used for the screening of small-molecule lead compounds in drug discovery; the two methods are complementary in that the measurements are performed with widely different experimental conditions. Here, we used the structure of the A 2A adenosine receptor (A 2A AR) complex with V-2006 (3-(4-amino-3-methylbenzyl)-7-(furan-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine) as the basis for the design of a fluorine-containing probe molecule, FPPA (4-(furan-2-yl)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-d]pyramidin-2amine), for binding studies with A 2A AR. A protocol of experimental conditions for drug screening and measurements of drug binding affinities using 1D 19 F-NMR observation of FPPA is validated with studies of known A 2A AR ligands. 19 F-NMR with FPPA is thus found to be a robust approach for the discovery of ligands with new core structures, which will expand the libraries of A 2A ARtargeting drug candidates.

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Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3)

Cited by 19 publications

References 44 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Adenosine A_2A Receptor (A_2AAR) Ligand Screening Using the ¹⁹F-NMR Probe FPPA

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Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3)

Cited by 19 publications

References 44 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPA

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Product

Resources

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Adenosine A_2A Receptor (A_2AAR) Ligand Screening Using the ¹⁹F-NMR Probe FPPA