Small molecules as modulators of regulated cell death against ischemia/reperfusion injury DOI
Dan‐Qian Chen, Yan Guo, Xin Li

et al.

Medicinal Research Reviews, Journal Year: 2022, Volume and Issue: 42(6), P. 2067 - 2101

Published: June 21, 2022

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

Language: Английский

The development of small-molecule inhibitors targeting HPK1 DOI

Lixin Zhou,

Tianyu Wang, Kuojun Zhang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 244, P. 114819 - 114819

Published: Oct. 4, 2022

Language: Английский

Citations

36
The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy DOI

Sven Malchow,

Alla Korepanova, Sanjay C. Panchal

et al.

ACS Chemical Biology, Journal Year: 2022, Volume and Issue: 17(3), P. 556 - 566

Published: Feb. 21, 2022

Hematopoietic progenitor kinase 1 (HPK1) is an MAP4K family member within the Ste20-like serine/threonine branch of kinome. HPK1 expression limited to hematopoietic cells and has a predominant role as negative regulator T cell function. Because central/dominant in negatively regulating function, long been center interest potential pharmacological target for immune therapy. The development small molecule inhibitor remains challenging because need high specificity relative other kinases, including additional members, that are required efficient activation. Here, we report identification selective potent chemical probe, A-745. In unbiased cellular kinase-binding assays, A-745 demonstrates excellent selectivity binding profile pharmacologically relevant concentrations. This translates vitro activation phenotype reminiscent Hpk1-deficient Hpk1-kinase-dead cells, augmented proliferation cytokine production. results from this work give path forward further developmental efforts generate inhibitors with properties immunotherapy.

Language: Английский

Citations

29
MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1 DOI Creative Commons
Yuqiong Chen, Su Li, Bo Guan

et al.

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 9, 2024

Abstract Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications Drp1 have been reported, among S-nitrosylation was recently introduced. However, detailed regulatory mechanism (SNO-Drp1) in cardiac microvascular dysfunction diabetes remains elusive. The present study revealed that mitogen-activated kinase 4 (MAP4K4) consistently upregulated diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 endothelial cells (CMECs), turn led disorder. Further studies confirmed MAP4K4 at human C644 (mouse C650) by inhibiting glutathione peroxidase (GPX4) expression, through stimulated ferroptosis diabetes. In contrast, inhibition via DMX-5804 significantly reduced ferroptosis, alleviated improved db/db mice reducing SNO-Drp1. parallel, C650A mutation abolished role promoting disorder dysfunction. conclusion, our findings demonstrate plays an important DCM reveal activation may act as downstream targets, representing potential therapeutic targets for DCM.

Language: Английский

Citations

8
Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity DOI Creative Commons
Wesley L. McKeithan,

Dries Feyen,

Arne A.N. Bruyneel

et al.

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(5), P. 813 - 821.e6

Published: Sept. 14, 2020

Language: Английский

Citations

45
Small molecules as modulators of regulated cell death against ischemia/reperfusion injury DOI
Dan‐Qian Chen, Yan Guo, Xin Li

et al.

Medicinal Research Reviews, Journal Year: 2022, Volume and Issue: 42(6), P. 2067 - 2101

Published: June 21, 2022

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

Language: Английский

Citations

25