Identification of 5-(2,3-Dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model

Li, Yueshan; Xiong, Yu; Zhang, Guo; Zhang, Liting; Yang, Wei; Yang, Jiao; Huang, Luyi; Qiao, Zeen; Zhang, Miao; Lin, Guifeng; Sun, Qiu; Niu, Ting; Chen, Lijuan; Niu, Dawen; Li, Linli; Yang, Shengyong

doi:10.1021/acs.jmedchem.8b01652

Cited by 38 publications

(27 citation statements)

References 33 publications

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“…RIPK1 has also been shown to regulate hematopoiesis (20)(21)(22), mediate inflammation (9,22), maintain chromosomal stability (23,24), and modulate the expression of immune checkpoint molecules such as PD-1 or PD-L1 (23), which are known to be upregulated in MDS after failure to hypomethylating agent (HMA) therapy (25). In addition, inhibition of RIPK1 has been hypothesized as a potential therapeutic mechanism in several malignancies (26,27).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes

et al. 2019

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Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and cytopenias due to uncontrolled programmed cell death. The presence of pro-inflammatory cytokines and constitutive activation of innate immunity signals in MDS cells suggest inflammatory cell death, such as necroptosis, may be responsible for disease phenotype. We evaluated 64 bone marrow samples from 55 patients with MDS or chronic myelomonocytic leukemia (CMML) obtained prior to (n=46) or after (n=18) therapy with hypomethylating agents (HMAs). RNA from sorted bone marrow CD34+ cells was isolated and subject to amplification and RNA-Seq. Compared to healthy controls, expression levels of MLKL (CMML: 2.09 log2FC, p=0.0013; MDS: 1.89 log2FC, p=0.003), but not RIPK1 or RIPK3, were significantly upregulated. Higher expression levels of MLKL were associated with lower hemoglobin levels at diagnosis (−0.19 log2FC per Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes

et al. 2019

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“…69 noma lung metastasis model. 75 In other tumor models, knockout of RIPK1, RIPK3, or MLKL genes in cancer cells significantly reduced their tumorigenicity, and necroptosis inhibitors could slow tumor growth. In colon and esophageal cancer patients, it was also found that the level of MLKL phosphorylation was negatively correlated with prognosis and survival time.…”

Section: Necrop Tos Is and Mali G Nant S K In Tumormentioning

confidence: 99%

Role of necroptosis in infection‐related, immune‐mediated, and autoimmune skin diseases

Liu

Tang

Zeng

et al. 2021

The Journal of Dermatology

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As the body's largest organ, the skin mainly acts as a physical barrier.It is the first line of defense against infection and injury, protecting the body from potential attacks by exotic organisms or toxic substances.At the same time, it is essential for the regulation of temperature and humidity, substance metabolism, and so forth. The skin is also an interface with the external environment, and its sensory ability helps individuals to interact amicably with the environment. Because it is directly exposed to the environment, it is frequently damaged. For this reason, skin diseases are very common. Although most skin diseases are not life-threatening, they may affect the appearance and make those with skin conditions vulnerable to harmful psychological effects. Therefore, research on the pathogenesis of skin diseases has traditionally been the direction of researchers' efforts.Cell death mechanisms can be traditionally classified into two types: programmed cell death (PCD) mechanisms and necrotic cell death. For many years, apoptosis was thought to be the only form of PCD. Until in the last decade, evidence suggested that additional forms of PCD exist, such as necroptosis (programmed necrosis).Necroptosis is a genetically controlled process of cell death and shares common morphological features with multiple PCD, such as increased cellular volume, organelle swelling, and plasma membrane destruction. However, they are activated by different triggers and are executed by different signaling pathways. Apoptosis does not cause an immune response because no cellular material is discharged into the interstitial space and phagocytes do not release inflammatory cytokines. Unlike apoptosis, necroptosis can elicit a strong adaptive immune response. Necroptosis has become an important pathological process of various diseases. At the same time, it is considered to be the mechanism of inhibiting tumor progression in tumor biology.Many excellent studies have explored the signal transduction cascade, pathophysiological correlation, and clinical disease models, such as neurodegeneration, 1 cancer, 2 virus infection, 3 cardiovascular disease, 4 and therapeutic interventions involving necroptosis. In recent years, an

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“…Although further studies are needed to elucidate the precise molecular mechanism through which RIPK1 and RIPK3 may mediate tumor cell extravasation, these observations reveal that RIPK1 and RIPK3 can be viewed as potential targets for developing therapeutic interventions against metastasis. Indeed, studies showed that blockage of RIPK1 kinase activity by Nec-1 or a different RIPK1 inhibitor significantly reduced tumor metastasis in vivo (Strilic et al, 2016;Li et al, 2018) (Table 1).…”

Section: Necroptosis In the Promotion Of Metastasismentioning

confidence: 99%

Complex roles of necroptosis in cancer

Zhu

Zhang

Yang

et al. 2019

J. Zhejiang Univ. Sci. B

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Necroptosis is a tightly regulated form of necrosis that requires the activation of receptor-interacting protein (RIP) kinases RIPK1 and RIPK3, as well as the RIPK3 substrate mixed lineage kinase domain-like protein (MLKL). Because of membrane rupture, necroptotic cells release damage-associated molecular patterns (DAMPs) that evoke immune responses. Necroptosis is emerging as an important cellular response in the modulation of cancer initiation, progression, and metastasis. Necroptosis of cancer cells is considered to be an immunogenic cell death capable of activating anti-tumor immunity. Necroptosis also participates in the promotion of myeloid cell-induced adaptive immune suppression and thus contributes to oncogenesis. In addition, necroptosis of endothelial cells and tumor cells is conducive to tumor metastasis. In this review, we summarize the current knowledge of the complex role of necroptosis in cancer and discuss the potential of targeting necroptosis components for cancer therapies.

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Identification of 5-(2,3-Dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model

Cited by 38 publications

References 33 publications

Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes

Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes

Role of necroptosis in infection‐related, immune‐mediated, and autoimmune skin diseases

Complex roles of necroptosis in cancer

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