The Bcr-Abl inhibitor GNF-7 inhibits necroptosis and ameliorates acute kidney injury by targeting RIPK1 and RIPK3 kinases

Qin, Xia; Hu, Longmiao; Shi, Shen-Nan; Chen, Xiaofei; Zhuang, Chunlin; Zhang, Wen; Jitkaew, Siriporn; Pang, Xiufeng; Yu, Jianqiang; Tan, Ye-Xiong; Wang, Hongyang; Cai, Zhenyu

doi:10.1016/j.bcp.2020.113947

Cited by 21 publications

(18 citation statements)

References 47 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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“… 447 In addition, it is worth noting that many of the clinical kinase inhibitors such as Bcr-Abl inhibitor also target RIPK1 and RIPK3 to improve the efficacy of current cancer-targeted therapies. 448 MEK inhibitor in combination with autophagy inhibitor can activate TAMs toward an immunogenic M1-like phenotype through STING/type I interferon pathway, which is an attractive therapeutic approach for PDA immunotherapy development. 449 During a phase III trial of patients with metastatic breast cancer, the receptor protein tyrosine kinase inhibitor sunitinib enhanced the efficacy of ICIs by inducing p62-mediated selective autophagy to downregulate tumor PD-L1 expression.…”

Section: New Advances In Targeting Autophagy Pyroptosis Ferroptosis A...mentioning

confidence: 99%

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Gao

Wang

Zhou

et al. 2022

Sig Transduct Target Ther

415

189

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In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune “cold” tumors into “hot” tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.

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“…GNF-7, previously identified as a kinase inhibitor for Bcl–Abl, demonstrates its efficacy as a dual kinase inhibitor for RIPK1 and RIPK3 and necrosome formation. Qin et al also highlight the more potent capacity of GNF-7 to inhibit necroptosis than the widely used RIPK1 inhibitor Nec-1 [ 175 ]. Other inhibitors include RIPK1-specific necrostatins, RIPK3-targeting molecules (GSK’872, GSK’843, dabrafenib), and the necrosulfonamide, which targets MLKL [ 175 , 176 , 177 , 178 ].…”

Section: Necroptosis In Kidney Cancermentioning

confidence: 99%

“…Qin et al also highlight the more potent capacity of GNF-7 to inhibit necroptosis than the widely used RIPK1 inhibitor Nec-1 [ 175 ]. Other inhibitors include RIPK1-specific necrostatins, RIPK3-targeting molecules (GSK’872, GSK’843, dabrafenib), and the necrosulfonamide, which targets MLKL [ 175 , 176 , 177 , 178 ].…”

Section: Necroptosis In Kidney Cancermentioning

confidence: 99%

No Time to Die: How Kidney Cancer Evades Cell Death

Ganini

Montanaro

Scimeca

et al. 2022

IJMS

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The understanding of the pathogenesis of renal cell carcinoma led to the development of targeted therapies, which dramatically changed the overall survival rate. Nonetheless, despite innovative lines of therapy accessible to patients, the prognosis remains severe in most cases. Kidney cancer rarely shows mutations in the genes coding for proteins involved in programmed cell death, including p53. In this paper, we show that the molecular machinery responsible for different forms of cell death, such as apoptosis, ferroptosis, pyroptosis, and necroptosis, which are somehow impaired in kidney cancer to allow cancer cell growth and development, was reactivated by targeted pharmacological intervention. The aim of the present review was to summarize the modality of programmed cell death in the pathogenesis of renal cell carcinoma, showing in vitro and in vivo evidence of their potential role in controlling kidney cancer growth, and highlighting their possible therapeutic value.

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The Bcr-Abl inhibitor GNF-7 inhibits necroptosis and ameliorates acute kidney injury by targeting RIPK1 and RIPK3 kinases

Cited by 21 publications

References 47 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

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

No Time to Die: How Kidney Cancer Evades Cell Death

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