Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors

Wu, S. C.; Xu, Liben; Wang, Xinhui; Yang, Qing; Wang, Jian; He, Sudan; Zhang, Xiaohu

doi:10.1016/j.bmcl.2022.128968

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…17 presents high affinity with RIPK2 (Kd = 5.9 nM) and high degree of discriminability towards receptor-interacting protein kinase 1 (RIPK1, Kd > 30,000 nM). Besides in vivo effectiveness, 17 displays good metabolic stability and no cytochrome P450 (CYP) inhibition ( Wu et al, 2022 ).…”

Section: Development On Ripk2 Inhibitors Has Achieved Initial Successmentioning

confidence: 99%

RIPK2: a promising target for cancer treatment

You

Wang²,

Chen

et al. 2023

Front. Pharmacol.

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As an essential mediator of inflammation and innate immunity, the receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is responsible for transducing signaling downstream of the intracellular peptidoglycan sensors nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2), which will further activate nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, leading to the transcription activation of pro-inflammatory cytokines and productive inflammatory response. Thus, the NOD2-RIPK2 signaling pathway has attracted extensive attention due to its significant role in numerous autoimmune diseases, making pharmacologic RIPK2 inhibition a promising strategy, but little is known about its role outside the immune system. Recently, RIPK2 has been related to tumorigenesis and malignant progression for which there is an urgent need for targeted therapies. Herein, we would like to evaluate the feasibility of RIPK2 being the anti-tumor drug target and summarize the research progress of RIPK2 inhibitors. More importantly, following the above contents, we will analyze the possibility of applying small molecule RIPK2 inhibitors to anti-tumor therapy.

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Section: Development On Ripk2 Inhibitors Has Achieved Initial Successmentioning

confidence: 99%

RIPK2: a promising target for cancer treatment

You

Wang²,

Chen

et al. 2023

Front. Pharmacol.

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“…Recently, Wu et al screened a novel scaffold of RIPK2 inhibitors from the ester prodrug 19 via a cyclization strategy. 111 Their structure−activity relationship (SAR) study led to the identification of inhibitor 20, the first tricyclic compound as a RIPK2 inhibitor (Figure 7). Inhibitor 20 displayed a high affinity for RIPK2 and inhibited RIPK2 kinase function in an ADP-Glo assay.…”

Section: Design Of Ripk2 Inhibitors: Strategies For Developing Clinic...mentioning

confidence: 99%

“…Optimization process of a RIPK2 inhibitor clinical candidate from GlaxoSmithKline (GSK). ,,, Abbreviations: F, bioavailability; IC 50 , half-maximal inhibitory concentration; PD, pharmacodynamic; PK, pharmacokinetic.…”

Section: Ripk2 Inhibitorsmentioning

confidence: 99%

Receptor Interacting Ser/Thr-Protein Kinase 2 as a New Therapeutic Target

Rivoal,

Dubuquoy,

Millet

et al. 2023

J. Med. Chem.

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Receptor interacting serine/threonine protein kinase 2 (RIPK2) is a downstream signaling molecule essential for the activation of several innate immune receptors, including the NOD-like receptors (NOD1 and NOD2). Recognition of pathogen-associated molecular pattern proteins by NOD1/2 leads to their interaction with RIPK2, which induces release of pro-inflammatory cytokines through the activation of NF-κB and MAPK pathways, among others. Thus, RIPK2 has emerged as a key mediator of intracellular signal transduction and represents a new potential therapeutic target for the treatment of various conditions, including inflammatory diseases and cancer. In this Perspective, first, an overview of the mechanisms that underlie RIPK2 function will be presented along with its role in several diseases. Then, the existing inhibitors that target RIPK2 and different therapeutic strategies will be reviewed, followed by a discussion on current challenges and outlook.

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