Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel

Haile, Pamela A.; Casillas, Linda; Bury, Michael J.; Mehlmann, John F.; Singhaus, Robert R.; Charnley, Adam K.; Hughes, Terry V.; DeMartino, Michael P.; Wang, Gren Z.; Romano, Joseph J.; Dong, Xiaoyang; Plotnikov, Nikolay V.; Lakdawala, Ami S.; Convery, M.A.; Votta, Bartholomew J.; Lipshutz, David B.; Desai, Biva M.; Swift, Brandon; Capriotti, Carol A.; Berger, Scott B.; Mahajan, Mukesh; Reilly, Michael; Rivera, Elizabeth J.; Sun, Helen H.; Nagilla, Rakesh; LePage, Carol; Ouellette, Michael T.; Totoritis, Rachel D.; Donovan, Brian T.; Brown, Barry S.; Chaudhary, Khuram W.; Gough, Peter J.; Bertin, John; Marquis, Robert W.

doi:10.1021/acsmedchemlett.8b00344

Cited by 32 publications

(40 citation statements)

References 23 publications

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“…Recently, groups including ours have reported that small molecule RIP2 inhibitors block proinflammatory signaling and reduce inflammation in preclinical models. − Together, these data support the notion that the NOD/RIP2 signaling pathways likely play a significant role in the pathogenesis of inflammatory diseases and that specific targeting of this pathway may have broad therapeutic value.…”

supporting

confidence: 61%

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

Haffner

Charnley

Aquino

et al. 2019

ACS Med. Chem. Lett.

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Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

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supporting

confidence: 61%

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

Haffner

Charnley

Aquino

et al. 2019

ACS Med. Chem. Lett.

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“…Many of these reports have presented in vitro studies that have demonstrated the importance of the ternary complex between the target protein, the PROTAC, and the E3 ligase complex in determining not only the degradation efficiency, but also introducing greater degradation selectivity as compared to the native binding selectivity of the target binding moiety of the corresponding PROTAC [33][34][35][36] . In the current work, we began with a highly potent and selective RIPK2 inhibitors already available as a result of previous RIPK2 lead optimization efforts 25,37 , and we were able to quickly demonstrate effective degradation of the target protein with PROTACs based on these inhibitors. It is noteworthy that the highly potent cellular degradation of RIPK2 by PROTAC 2 (pDC 50 = 9.4 ± 0.1) is achieved from a less potent biochemical RIPK2 IC 50 of 10 nM.…”

Section: Discussionmentioning

confidence: 99%

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

et al. 2020

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Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

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“…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

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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.

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Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel

Cited by 32 publications

References 23 publications

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

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

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

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