Discovery of bardoxolone derivatives as novel orally active necroptosis inhibitors

Wang, Yuanyuan; Ma, Hao; Huang, Jian; Yao, Zhengguang; Yu, Jianqiang; Zhang, Wannian; Zhang, Lichao; Wang, Zhibin; Zhuang, Chunlin

doi:10.1016/j.ejmech.2020.113030

Cited by 24 publications

(22 citation statements)

References 49 publications

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“…The ant-inecroptosis activity was measured using a chemiluminescence assay following our previous studies 28 , 29 , 31 , 32 , 33 . Different substitutions (R 1 ) at the C-7-position were introduced in the first round of optimizations ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Zhu

Meng

et al. 2021

Acta Pharmaceutica Sinica B

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Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 ( 5 ) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3. In this study, using ligand-based substituent-anchoring design strategy, we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3. Among them, a conformational constrained fluorine-substituted derivative ( 25 ) exhibited 333-fold selectivity for RIP1 ( K d = 15 nmol/L) than RIP3 ( K d > 5000 nmol/L). This compound showed highly potent activity against cell necroptosis (EC 50 = 8 nmol/L) and systemic inflammatory response syndrome (SIRS) induced by TNF- α in vivo. Especially, it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC. Taken together, the highly potent, selective, orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.

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Section: Resultsmentioning

confidence: 99%

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Zhu

Meng

et al. 2021

Acta Pharmaceutica Sinica B

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“…A recent study suggested that it could effectively block the activation of RIPK1 kinase activity via inhibiting HSP90. 189,190 Geldanamycin (GA) is one of benzoquinone ansamycins discovered in the culture filtrates of Streptomyces hygroscopicus var. geldanus var.…”

Section: Inhibitors Of Ripk1mentioning

confidence: 99%

Targeting Necroptosis as a Promising Therapy for Alzheimer’s Disease

Zhao

Liu

et al. 2022

ACS Chem. Neurosci.

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Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder featured by memory loss and cognitive default. However, there has been no effective therapeutic approach to prevent the development of AD and the available therapies are only to alleviate some symptoms with limited efficacy and severe side effects. Necroptosis is a new kind of cell death, being regarded as a genetically programmed and regulated pattern of necrosis. Increasing evidence reveals that necroptosis is tightly related to the occurrence and development of AD. This review aims to summarize the potential role of necroptosis in AD progression and the therapeutic capacity of targeting necroptosis for AD patients.

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“…NTB451 significantly suppresses necroptosis through inhibiting MLKL phosphorylation, oligomerization, and RIPK1/RIPK3 complex 127 . Compound 20, a kind of bardoxolone derivative, inhibits necrosome formation by regulating Hsp90 to suppress RIPK1 and RIPK3 phosphorylation in necroptotic cells against IR injury 128 …”

Section: Necroptosis and Small Molecules In Ir Injurymentioning

confidence: 99%

Small molecules as modulators of regulated cell death against ischemia/reperfusion injury

Chen

Guo

et al. 2022

Medicinal Research Reviews

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Ischemia/reperfusion (IR) injury contributes to disability and mortality worldwide. Due to the complicated mechanisms and lack of proper therapeutic targets, few interventions are available that specifically target the pathogenesis of IR injury. Regulated cell death (RCD) of endothelial and parenchymal cells is recognized as the promising intervening target. Recent advances in IR injury suggest that small molecules exhibit beneficial effects on various RCD against IR injury, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis, and parthanatos. Here, we describe the mechanisms behind these novel promising therapeutic targets and explain the machinery powering the small molecules. These small molecules exert protection by targeting endothelial or parenchymal cells to alleviate IR injury. Therapies of the ideal combination of small molecules targeting multiple cell types have shown potent synergetic therapeutic effects, laying the foundation for novel strategies to attenuate IR injury.

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Discovery of bardoxolone derivatives as novel orally active necroptosis inhibitors

Cited by 24 publications

References 49 publications

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Targeting Necroptosis as a Promising Therapy for Alzheimer’s Disease

Small molecules as modulators of regulated cell death against ischemia/reperfusion injury

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