Home
Drugs
Targets
Pathways
Ontologies
Cyp450s
Adv.search
Help/FAQ

Drug-Target Interaction

Drug

show drug details
PubChem ID:3058739
Structure:
Synonyms:
(2S,3S)-2-Amino-1,3-octadecanediol
(2S,3S)-2-aminooctadecane-1,3-diol
1,3-Octadecanediol, 2-amino- (2S,3S)
15639-50-6
2S,3S-Dihydrosphingosine
AC1MHW52
Bio1_000031
Bio1_000520
Bio1_001009
Bio2_000012
Bio2_000492
BML3-D10
BSPBio_001292
CBiol_001745
D05784
D7033_SIGMA
DL-threo-1,3-Dihydroxy-2-aminooctadecane
DL-threo-Dihydrosphingosine
HMS1361A14
HMS1791A14
HMS1989A14
IDI1_033762
KBio2_000012
KBio2_002580
KBio2_005148
KBio3_000023
KBio3_000024
KBioGR_000012
KBioSS_000012
L-threo sphinganine (2S, 3S)
L-threo-2-Amino-1,3-octadecanediol
L-threo-dihydrosphingosine (d18:0)
LMSP01080055
NCGC00161368-01
NCGC00161368-02
NCGC00161368-03
NSC714503
Safingol
Safingol (USAN/INN)
SMP2_000060

Target

show target details
Uniprot ID:PK3C3_HUMAN
Synonyms:
Phosphatidylinositol 3-kinase catalytic subunit type 3
Phosphatidylinositol 3-kinase p100 subunit
Phosphoinositide-3-kinase class 3
PI3-kinase type 3
PI3K type 3
PtdIns-3-kinase type 3
EC-Numbers:2.7.1.137
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

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

References:

19098447
Safingol (L-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway.. Jesse Coward; Grazia Ambrosini; Elgilda Musi; Jean-Philip Truman; Adriana Haimovitz-Friedman; Jeremy C Allegood; Elaine Wang; Alfred H MerrillJr; Gary K Schwartz (2009) Autophagy display abstract
Safingol, the synthetic L-threo-stereoisomer of endogenous (D-erythro-) sphinganine, is an inhibitor of protein kinase C and sphingosine kinase in vitro, and in some cell types has been implicated in ceramide generation and induction of apoptosis. Utilizing electron microscopy, acridine orange staining, and immunoblot and fluorescent localization studies of the myosin light chain-associated protein (LC3), we determined that safingol induces cell death of an exclusively autophagic character and lacking any of the hallmarks of apoptosis. Safingol inhibited PKCbeta-I, PKC delta and PKC epsilon, and inhibited phosphorylation of critical components of the PI3k/Akt/mTOR pathway (Akt, p70S6k and rS6) and the MAPk pathway (ERK). Inhibition of PI3k with LY294002 or suppression of PKC delta and PKC epsilon with siRNA in HCT-116 cells induced autophagy, though not to the extent caused by safingol. Conversely, activation of PKCs with phorbol 12,13-dibutyrate (PDBu) or transient transfection of a constitutively active form of Akt each reduced safingol's autophagic induction, but not completely, indicating that Akt- and PKC-dependent pathways both contribute partially and independently to safingol-induced autophagy. Accordingly, combining siRNA depletion of PKC epsilon with LY294002 inhibition of PI3k induced autophagy to a degree comparable to safingol. Liquid chromatography, electrospray tandem mass spectrometry analysis indicated that safingol did not elevate levels of any endogenous sphingolipids previously shown to induce autophagy (ceramide, sphingosine-1-phosphate and dihydroceramide); therefore, these effects may be due to safingol per se or another metabolite. Thus, our studies establish that safingol induces autophagy through inhibition of PKCs and PI3k by safingol directly rather than via changes in endogenous sphingolipids.