Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0378)
Name
RR-11a
Synonyms
RR-11a; (5S,8S,E)-2,5-Dioxopyrrolidin-1-yl 11-(2-amino-2-oxoethyl)-5,8-dimethyl-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,11-tetraazapentadec-13-en-15-oate; 1361390-56-8; SCHEMBL10044438; AKOS040736812; HY-112205; CS-0044123

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Structure
3D MOL
2D MOL
Formula
C24H28N6O10
IUPAC Name
(2,5-dioxopyrrolidin-1-yl) (E)-4-[(2-amino-2-oxoethyl)-[[(2S)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoyl]amino]amino]-4-oxobut-2-enoate
Canonical SMILES
CC(C(=O)NN(CC(=O)N)C(=O)C=CC(=O)ON1C(=O)CCC1=O)NC(=O)C(C)NC(=O)OCC2=CC=CC=C2
InChI
InChI=1S/C24H28N6O10/c1-14(27-24(38)39-13-16-6-4-3-5-7-16)22(36)26-15(2)23(37)28-29(12-17(25)31)18(32)10-11-21(35)40-30-19(33)8-9-20(30)34/h3-7,10-11,14-15H,8-9,12-13H2,1-2H3,(H2,25,31)(H,26,36)(H,27,38)(H,28,37)/b11-10+/t14-,15-/m0/s1
InChIKey
OBTLSXIZYGMZRE-BWLFODOESA-N
PubChem CID
88556687
Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Acute kidney failure ICD-11: GB60
 Disease Info 
Responsed Regulator Legumain (LGMN) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
The genetic background of embryonic stem cells and the Flp mice used in this experiment was C57BL/6. Mice were randomly separated into experimental groups and control groups. (1) Bilateral IRI: mice (male, 8-10 weeks old) on the lgmnKO background or littermate control mice were anesthetized by an intraperitoneal (i.p.) injection of chloral hydrate and placed on a warm pad to retain their body temperature. A bilateral flank incision was made, both sides of the renal vessels were occluded with clamps for 40 min followed by removing the clamps to induce blood reperfusion. The same procedure was performed in the control group without vessel clamping. (2) Nephrotoxic folic acid-induced AKI: mice (female, 12-14 weeks old) received a single i.p. injection of folic acid at 250 mg/kg in 0.3 mol/L sodium bicarbonate or the vehicle. For therapeutic experiments, RR-11a was freshly dissolved in saline. Mice were administered an i.p. injection of 20 mg/kg RR-11a or the vehicle before ischemia.

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Response regulation Legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in acute kidney injury (AKI). Legumain inhibitor RR-11a attenuates ferroptosis and tubular injury induced by ischemia-reperfusion injury (IRI).
References
Ref 1 Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI. Cell Death Dis. 2021 Jan 11;12(1):65. doi: 10.1038/s41419-020-03362-4.