A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

Yoon, Sae‐Bom; Hong, Hyowon; Lim, H.; Choi, Ji Hye; Choi, Yoon Pyo; Seo, Seong Wook; Lee, Hyuk Woo; Chae, Chong Hak; Park, Woo-Kyu; Kim, Hyun Young; Jeong, Daeyoung; De, Tran Quang; Myung, Chang‐Seon; Cho, Heeyeong

doi:10.1016/j.apsb.2022.12.001

Cited by 19 publications

(8 citation statements)

References 97 publications

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“…In a mouse model of rheumatoid arthritis, treatment with KIC-0101 significantly improves cartilage damage and inflammation. 591 Additionally, researchers have discovered that Perillyl alcohol (POH) effectively ameliorates arthritis in rats by modulating the TLR4/NF-κB signaling pathway. 592 The current research has identified several novel targets for treating osteoarthritis (OA) through the NF-κB pathway.…”

Section: Strategies For Targeting Nf-κb Signaling In Human Diseasesmentioning

confidence: 99%

NF-κB in biology and targeted therapy: new insights and translational implications

Guo,

Jin,

Chen

et al. 2024

Sig Transduct Target Ther

172

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NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

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Section: Strategies For Targeting Nf-κb Signaling In Human Diseasesmentioning

confidence: 99%

NF-κB in biology and targeted therapy: new insights and translational implications

Guo,

Jin,

Chen

et al. 2024

Sig Transduct Target Ther

172

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“…In addition to its antitumor properties, this compound holds promise in effectively treating immunological disorders, providing an alternative therapeutic approach (Figure 8C). 106 4.2.4. PIM/MNK.…”

Section: Irak4/pim-1mentioning

confidence: 99%

“…This effect not only demonstrated efficacy against the malignancy of diffuse large B-cell lymphoma (DLBCL) but also showed potential in alleviating symptoms of rheumatoid arthritis (RA). In addition to its antitumor properties, this compound holds promise in effectively treating immunological disorders, providing an alternative therapeutic approach (Figure C) …”

Section: Pim Inhibitors In Publicationsmentioning

confidence: 99%

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Chen,

Mao,

Ren

et al. 2024

J. Med. Chem.

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Proviral integration sitea for Moloney-murine leukemia virus (PIM) kinases are a family of highly conserved serine/tyrosine kinases consisting of three members, PIM-1, PIM-2, and PIM-3. These kinases regulate a wide range of substrates through phosphorylation and affect key cellular processes such as transcription, translation, proliferation, apoptosis, and energy metabolism. Several PIM inhibitors are currently undergoing clinical trials, such as a phase I clinical trial of Uzanserti (5) for the treatment of relapsed diffuse large B-cell lymphoma that has been completed. The current focus encompasses the structural and biological characterization of PIM, ongoing research progress on small-molecule inhibitors undergoing clinical trials, and evaluation analysis of persisting challenges in this field. Additionally, the design and discovery of small-molecule inhibitors targeting PIM in recent years have been explored, with a particular emphasis on medicinal chemistry, aiming to provide valuable insights for the future development of PIM inhibitors. ■ SIGNIFICANCEA concise summary of research in the field of PIM inhibition for cancer, with a focus on medicinal chemistry, is presented. An analysis of current compounds entering clinical trials highlights existing issues and provides viewpoints on potential solutions. Future prospects and recommendations for development are discussed, emphasizing the need for unique perspectives and analyses in medicinal chemistry to stimulate critical thinking, expand understanding, and advance research in this field.

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“…Accordingly, it is suggested that emavusertib is an inhibitor of IRAK4 or it can reduce its activity by other mechanisms [ 108 ]. KIC-0101 is a dual IRAK4/PIM1 inhibitor that has been reported to suppress proinflammatory cytokine induction in vitro and ameliorated cartilage damage and inflammation in vivo rheumatoid arthritis mouse models [ 109 ].…”

Section: Targeting Iraks Represents An Attractive Strategy To Counter...mentioning

confidence: 99%

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

2023

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients.

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A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

Cited by 19 publications

References 97 publications

NF-κB in biology and targeted therapy: new insights and translational implications

NF-κB in biology and targeted therapy: new insights and translational implications

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

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