Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors

Haffner, Curt D.; Charnley, Adam K.; Aquino, Christopher; Casillas, Linda; Convery, M.A.; Cox, Julie A.; Elban, Mark A.; Goodwin, Nicole C.; Gough, Peter J.; Haile, Pamela A.; Hughes, Terry V.; Knapp-Reed, Beth; Kreatsoulas, Constantine; Lakdawala, Ami S.; Li, Huijie; Lian, Yiqian; Lipshutz, David B.; Mehlmann, John F.; Ouellette, Michael T.; Romano, Joseph J.; Shewchuk, Lisa M.; Shu, Arthur Y. L.; Votta, Bartholomew J.; Zhou, Hongmin; Bertin, John; Marquis, Robert W.

doi:10.1021/acsmedchemlett.9b00141

Cited by 21 publications

(12 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This work is the first to demonstrate the efficacy and modulatory activity of a RIP2-targeting compound using a clinically relevant model of allergic asthma. Numerous inhibitors have both been discovered and developed for modulation of RIP2 activity (23,(41)(42)(43)(44)(45)(46)(47)(48)(49). The RIP2 inhibitor used in this study, GSK583, has been reported to be highly selective and exhibits strong potency even in vivo (23,45).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

2020

View full text Add to dashboard Cite

Exposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely Th2 and Th17 dominant, and a number of innate immune receptors have been identified that recognize HDM to initiate these responses. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic sensor of peptidoglycan, which is important for Th2 and Th17 polarization. NOD2 mediates its signaling through its downstream effector kinase, receptorinteracting serine/threonine protein kinase 2 (RIP2). We have previously shown that RIP2 promotes HDM-associated allergic airway inflammation and Th2 and Th17 immunity, acting early in the HDM response and likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while reducing the Th2 immune response. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2-targeted therapies. ImmunoHorizons, 2020, 4: 825-836.

show abstract

Section: Discussionmentioning

confidence: 99%

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

2020

View full text Add to dashboard Cite

show abstract

“…This work is the first to demonstrate the efficacy and modulatory activity of a RIP2 targeting compound using a clinically relevant model of allergic asthma. Numerous inhibitors have both been discovered and developed for modulation of RIP2 activity (23,(35)(36)(37)(38)(39)(40)(41)(42)(43). The RIP2 inhibitor utilized in this study, GSK583, has been reported to be highly selective and exhibits strong potency even in vivo (23,39).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

Miller

Shehat

Tigno-Aranjuez

2020

Preprint

View full text Add to dashboard Cite

AbstractExposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely T helper cell type 2 (Th2) dominant and a number of innate immune receptors have been identified which recognize HDM to initiate a Th2 response. Nucleotide-binding Oligomerization Domain-containing Protein 2 (NOD2) is a cytosolic sensor of peptidoglycan which is important for Th2 polarization. NOD2 mediates its signaling through its downstream effector kinase, Receptor-interacting Serine/Threonine Protein Kinase 2 (RIP2). We have previously shown that RIP2 is important in promoting HDM-associated allergic airway inflammation and Th2 immunity. In particular, we demonstrated that the effects of RIP2 were important early in the HDM response, likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while skewing the immune response from Th2 towards Th1. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2 targeted therapies.

show abstract

“…In the following compounds, the 1,3‐diazepine scaffold was not a crucial element of the structure and could be replaced by smaller rings without affecting their potency. In Figure 23 are reported compounds stimulating AMPK 170 and modulating ɣ‐secretase 171 activities, as well as inhibitors of human β‐secretase (BACE1), 172,173 polymerase bacteriophage T7 ARN, 174,175 Factor Xa, 176 RIP2, 177 phosphatidylcholine‐preferring phospholipase C, 178 acetylcholinesterase, 179,180 and squalene synthase 181 …”

Section: 3‐diazepine Derivatives As Enzyme Inhibitorsmentioning

confidence: 99%

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Malki

Martinez

Masurier

2021

Medicinal Research Reviews

View full text Add to dashboard Cite

Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

show abstract

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors

Cited by 21 publications

References 34 publications

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Contact Info

Product

Resources

About