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Drug-Target Interaction

Drug

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PubChem ID:5478883
Structure:
Synonyms:
(3S,4S)-3-hydroxy-4-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-3-methy
1lyb
1sme
26305-03-3
3-HYDROXY-4-ISOBUTYL-4-[AMINOCARBONYLETHYL(AMINO CARBONYL-2-HYDROXY-5-METHYLHEXYL)TRI(AMINOCARBONYL ISOBUTYL)]BUTANOIC ACID
4er2
6apr
AB00513830
AC1NUHKG
AIDS-000247
AIDS000247
Bio1_000404
Bio1_000893
Bio1_001382
Bio2_000340
Bio2_000820
BPBio1_000364
BRD-K13571841-001-03-7
BSPBio_000330
BSPBio_001000
CHEMBL296588
CPD-11291
D03818
HMS1362B21
HMS1792B21
HMS1990B21
HMS2096A12
HMS2233I07
IDI1_002095
IHN
Iva-Val-Val-Sta-Ala-Sta-OH
KBio2_000340
KBio2_002908
KBio2_005476
KBio3_000679
KBio3_000680
KBioGR_000340
KBioSS_000340
MLS000069747
MLS002207302
MLS002222329
MolPort-006-124-949
N-[(3-Methyl-1-oxobutyl)-L-valyl-L-valyl-4-amino-3-hydroxy-6-methylheptanoyl-L-alanyl]-4-amino-3-hydroxy-6-methylheptanoic acid
NCGC00161670-01
NCGC00161670-02
NCGC00161670-03
NCGC00161670-04
NSC272671
Pepstatin
Pepstatin (USAN/INN)
Pepstatin A
Pepstatine
Prestwick3_000405
SMR000059191
SMR001307268
UPCMLD-DP141
UPCMLD-DP141:001
UPCMLD-DP141:002

Target

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Uniprot ID:ICE_DROME
Synonyms:
Caspase
drICE
EC-Numbers:3.4.22.-
Organism:Drosophila melanogaster
Fruit fly
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

11423908
Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells.. Y Zang; R L Beard; R A Chandraratna; J X Kang (2001) Cell death and differentiation display abstract
The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid (AHPN/CD437) has been proven to be a potent inducer of apoptosis in a variety of tumor cell types. However, the mechanism of its action remains to be elucidated. Recent studies suggest that the lysosomal protease cathepsin D, when released from lysosomes to the cytosol, can initiate apoptosis. In this study, we examined whether cathepsin D and free radicals are involved in the CD437-induced apoptosis. Exposure of human leukemia HL-60 cells to CD437 resulted in rapid induction of apoptosis as indicated by caspase activation, phosphatidylserine exposure, mitochondrial alterations and morphological changes. Addition of the antioxidants alpha-tocopherol acetate effectively inhibited the CD437-induced apoptosis. Measurement of the intracellular free radicals indicated a rise in oxidative stress in CD437-treated cells, which could be attenuated by alpha-tocopherol acetate. Interestingly, pretreatment of cells with the cathepsin D inhibitor pepstatin A blocked the CD437-induced free radical formation and apoptotic effects, suggesting the involvement of cathepsin D. However, Western blotting revealed no difference in cellular quantity of any forms of cathepsin D between control cells and CD437-treated cells, whereas immunofluorescence analysis of the intracellular distribution of cathepsin D showed release of the enzyme from lysosomes to the cytosol. Labeling of lysosomes with lysosomotropic probes confirmed that CD437 could induce lysosomal leakage. The CD437-induced relocation of cathepsin D could not be prevented by alpha-tocopherol acetate, suggesting that the lysosomal leakage precedes free radical formation. Furthermore, a retinoic acid nuclear receptor (RAR) antagonist failed to block these effects of CD437, suggesting that the action of CD437 is RAR-independent. Taken together, these data suggest a novel lysosomal pathway for CD437-induced apoptosis, in which lysosomes are the primary target and cathepsin D and free radicals act as death mediators.