Author: Huang, Chuting ; Wang, Lexuan ; Guo, Peilin ; Qiao, Chaoqiang ; Shi, Changhong ; Zhang, Ruili ; Bao, Weier ; Wang, Zhongliang ; Rao, Zhiping ; Chen, Zhuang ; Wei, Wei ; Tan, Dengxu ; Jia, Qian

AbstractCysteine metabolism is a key determinant of the defense against ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Blocking cysteine metabolism may trigger potent ferroptosis in PDAC cells by generating lipid peroxides during tumor metabolic processes. However, current methods to limit cysteine availability fall short, failing to efficiently block cysteine metabolism due to inadequate tumor targeting and compensatory cysteine sources. Inspired by sulfur‐metabolizing bacteria, synthetic biology to develop an engineered bacterium capable of directly depleting cysteine to block its metabolism is used. Acting as a living drug, these engineered bacteria colonize the tumor and continuously produce engineered cyst(e)inase enzyme (CGL) under the stimulation of tumor hypoxia. The CGL exhausts the substrate cysteine, completely impeding cysteine metabolism. This process dismantles the ferroptosis defense system in PDAC cells, triggers potent ferroptosis, and achieves efficient treatment. The results demonstrate that engineered bacteria designed for cysteine metabolism modulation possess unparalleled advantages in efficacy, persistence, and precision in blocking cysteine metabolism, making them highly suitable for effective ferroptosis treatment of PDAC.

22 Jan 2025·Biochemical Journal

Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury

Article

Author: McRae, Jennifer L. ; Ierino, Francesco L. ; Bongoni, Anjan K. ; Pefanis, Aspasia ; Murphy, James M. ; Cowan, Peter J. ; Salvaris, Evelyn J. ; Fisicaro, Nella

Ischemia-reperfusion injury (IRI) occurs when the blood supply to an organ is temporarily reduced and then restored. Kidney IRI is a form of acute kidney injury (AKI), which often progresses to kidney fibrosis. Necroptosis is a regulated necrosis pathway that has been implicated in kidney IRI. Necroptotic cell death involves the recruitment of the RIPK1 and RIPK3 kinases and the activation of the terminal effector, the mixed lineage kinase domain-like (MLKL) pseudokinase. Phosphorylated MLKL causes cell death by plasma membrane rupture, driving ‘necroinflammation’. Owing to their apical role in the pathway, RIPK1 and RIPK3 have been implicated in the development of kidney fibrosis. Here, we used a mouse model of unilateral kidney IRI to assess whether the inhibition of RIPK1 or RIPK3 kinase activity reduces AKI and the progression to kidney fibrosis. Mice treated with the RIPK1 inhibitor Nec-1s, either before or after IR, showed reduced kidney injury at 24 hr compared with controls, whereas no protection was offered by the RIPK3 inhibitor GSK´872. In contrast, treatment with either inhibitor from days 3 to 9 post-IR reduced the degree of kidney fibrosis at day 28. These findings further support the role of necroptosis in IRI and provide important validation for the contribution of both RIPK1 and RIPK3 catalytic activities in the progression of kidney fibrosis. Targeting the necroptosis pathway could be a promising therapeutic strategy to mitigate kidney disease following IR.

15 Jan 2025·ACS Chemical Neuroscience

Development and Evaluation in Rat and Monkey of a Candidate Homochiral Radioligand for PET Studies of Brain Receptor Interacting Protein Kinase 1: [¹⁸F](S)-1-(5-(3-Fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one

Article

Author: Maqbool, Mudasir ; Telu, Sanjay ; Wu, Shawn ; Innis, Robert B. ; Jana, Susovan ; Long, Priscilla ; Pike, Victor W. ; Yan, Xuefeng ; Liow, Jeih-San ; Zoghbi, Sami S. ; Jakobsson, Jimmy E. ; Lee, Adrian C.

Receptor interacting protein kinase 1 (RIPK1) crucially upregulates necroptosis and is a key driver of inflammation. An effective PET radioligand for imaging brain RIPK1 would be useful for further exploring the role of this enzyme in neuroinflammation and for assisting drug discovery. Here, we report our progress on developing a PET radioligand for RIPK1 based on the phenyl-1H-dihydropyrazole skeleton of a lead RIPK1 inhibitor, GSK'963. The most potent inhibitor from a small structure-activity relationship study,(S)-1-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one ((S)-SJ1058 or (S)-5d), was labeled with no-carrier-added fluorine-18 (t_1/2 = 109.8 min) from a homochiral meta-tri-n-butylstannane precursor [(S)-11c] in 10-15% formulated yields. The lipophilicity measured for [¹⁸F](S)-SJ1058 was moderate (log D_7.4 = 3.00) and conducive to good brain permeability. PET scans with [¹⁸F](S)-SJ1058 in healthy monkeys under baseline and preblock conditions with a RIPK1 inhibitor, either Nec-1s or GSK'963, demonstrated high peak radioactivity uptake in the brain (3.1-3.9 SUV) but no evidence of in vivo RIPK1-specific binding. Moreover, [¹⁸F](S)-SJ1058 did not detect neuroinflammation in rats on day 1 and day 8 after systemic lipopolysaccharide administration. We conclude that [¹⁸F](S)-SJ1058 is unpromising for imaging human brain RIPK1 in neuroinflammation. Higher-affinity radioligands may be needed for this purpose.

100 Deals associated with Nec-1s

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Central Nervous System Diseases	Preclinical	China	Shanghai Jiao Tong University School of Medicine	24 Jan 2023
Central Nervous System Diseases	Preclinical	China	Shanghai Institute of Organic Chemistry	24 Jan 2023

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

Nec-1s

Overview

Basic Info

Structure/Sequence

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation