CR131-b 0.005μM R08 exp474

Inhibits EIF4A, blocks translation by trapping EIF4A on mRNA at poly-purine sites

Class / Subclass 1: Proteostasis / Translation Inhibitor

Compound References

PubChem Name: (1R,2R,3S,3Ar,8bS)-1,8b-dihydroxy-N,6,8-trimethoxy-3a-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide
Synonyms: N/A
CAS #: 1352914-52-3
PubChem CID: 56946209
IUPAC: (1R,2R,3S,3aR,8bS)-1,8b-dihydroxy-N,6,8-trimethoxy-3a-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide
INCHI Name: InChI=1S/C28H29NO8/c1-33-18-12-10-17(11-13-18)28-23(16-8-6-5-7-9-16)22(26(31)29-36-4)25(30)27(28,32)24-20(35-3)14-19(34-2)15-21(24)37-28/h5-15,22-23,25,30,32H,1-4H3,(H,29,31)/t22-,23-,25-,27+,28+/m1/s1
INCHI Key: KLSIFOJPWJBRFH-GWNOIRNCSA-N
Molecular Weight: 507.5
Canonical SMILES: COC1=CC=C(C=C1)C23C(C(C(C2(C4=C(O3)C=C(C=C4OC)OC)O)O)C(=O)NOC)C5=CC=CC=C5
Isomeric SMILES: COC1=CC=C(C=C1)[C@]23[C@@H]([C@H]([C@H]([C@]2(C4=C(O3)C=C(C=C4OC)OC)O)O)C(=O)NOC)C5=CC=CC=C5
Molecular Formula: C28H29NO8

Compound Supplier

Supplier Name: In house - McGill University - Jerry Pelletier group
Catalog #: N/A
Lot #: N/A

Compound Characterization

HRMS (ESI-TOF) m/z: (M-H)- Calcd for C28 H29 N O8 506.18204; found 506.18321

Dose Response Curve

Platform ID: CR131B
Min: -2.5197; Max: 93.9504

IC	Concentration (µM)
IC10	0.0001
IC20	0.0006
IC30	0.0020
IC40	0.0051
IC50	0.0122
IC60	0.0293
IC70	0.0762
IC80	0.2443
IC90	1.4100

Screen Summary

Round: 08
Dose: 5nM
Days of incubation: 8
Doublings: 1.0
Numbers of reads: 19941458

Sensitive/Resistant hits (FDR<0.05)	CRANKS	Score Plot	Top 30 Genes	Screen Similarity	Top 30 Sensitive GO terms	Top 30 Resistant GO terms
3/44	Scores	View	View	View	View	View

Gene	CRANKS Score	FDR
NRAS	-3.85	<0.01
NPRL3	-3.35	0.01
NSUN5	-2.84	0.08
ZNF830	-2.68	0.04
QRICH1	-2.51	0.08
NHP2L1	-2.41	0.32
OTUB1	-2.41	0.19
CDK2	-2.35	0.16
YBX3	-2.32	0.23
RHBDD3	-2.29	0.19
DDX23	-2.23	0.51
RPS28	-2.23	0.40
CCM2	-2.23	0.22
AURKB	-2.20	0.51
DDX3X	-2.18	0.23
CDC73	-2.16	0.30
GOLGA6L1	-2.15	0.60
ZBTB7A	-2.15	0.25
LOC200726	-2.14	0.25
FIBP	-2.12	0.26
SZT2	-2.11	0.26
ESPL1	-2.10	0.37
CHRNB3	-2.10	0.26
BCL2	-2.09	0.26
BRCA1	-2.09	0.32
PSIP1	-2.08	0.26
SRSF3	-2.07	0.30
TLR9	-2.05	0.29
MS4A13	-2.05	0.63
PRKCE	-2.04	0.29
SCD	2.56	0.02
N6AMT1	2.59	0.07
INTS10	2.62	<0.01
GNA13	2.63	<0.01
MRPS5	2.65	0.01
FBXO11	2.67	<0.01
FECH	2.70	<0.01
BCL2L11	2.77	<0.01
IKZF1	2.78	<0.01
GPATCH8	2.83	<0.01
RABIF	3.03	<0.01
COX7B	3.03	<0.01
ELP6	3.06	0.00
TP53	3.06	<0.01
DENND4A	3.21	<0.01
DAZAP1	3.28	0.00
SF1	3.33	<0.01
IKZF2	3.41	0.00
PMAIP1	3.44	0.00
KLF16	3.49	0.00
VDAC2	3.76	0.00
CYCS	4.07	0.00
ALAS1	4.29	0.00
CCAR1	4.29	0.00
MARCH5	4.36	0.00
CASP9	4.44	0.00
APAF1	4.47	0.00
HCCS	4.62	0.00
BAK1	7.44	0.00
EIF4A2	7.88	0.00

Screen	Correlation	Plot
MS023 7μM R03 exp135	0.101	View
PU-H71 1μM R08 exp515	0.095	View
Doxorubicin 0.02μM R08 exp478	0.093	View
Hippuristanol 0.12μM R08 exp488	0.091	View
Staurosporine 0.02μM R08 exp524	0.089	View
Hippuristanol 0.12μM R08 exp489 no dilution day6	0.088	View
Thimerosal 0.85μM R08 exp529	0.084	View
GSK-J4 1.5μM R08 exp441	0.082	View
GSK626616 14μM R08 exp485	0.08	View
SNS-032 15μM R08 exp443	0.079	View
JQ1 0.8μM R08 exp435	0.079	View
Mitomycin-C 0.06μM R08 exp503	0.078	View
THZ1 0.06μM R08 exp531	0.077	View
Olaparib 4μM R08 exp512	0.076	View
MS023 2μM R03 exp134	0.076	View
Dorsomorphin 5μM R07 exp357	0.075	View
TIC10 10μM R08 exp532	0.074	View
Tanespimycin 14μM R08 exp527	0.072	View
Etoposide 0.3μM R05 exp199	0.068	View
Hinokiflavone 12μM R08 exp487	0.067	View
Latrunculin-B 10μM R07 exp374	0.061	View
ONC212 0.15μM R08 exp513	0.06	View
Etoposide 1μM R00 exp19	0.058	View
Quercetin 20μM R08 exp517	0.058	View
Pimelic-diphenylamide-106 5μM R00 exp28	0.057	View
RO-3307 4.7μM R02 exp80	0.057	View
Rotenone 0.07μM R08 exp431	0.057	View
Hydroxyurea 100μM R07 exp329	0.056	View
iCRT14 30μM R08 exp492	0.055	View
Thapsigargin 0.005μM R07 exp407	0.052	View
Dynasore 7μM R08 exp436	0.052	View
Benzoate 20000μM R08 exp456	0.084	View
AICAR 240μM R05 exp211	0.08	View
Aphidicolin 0.4μM R08 exp440	0.078	View
Artemisinin 50μM R08 exp450	0.076	View
Bleomycin 5μM R08 exp459	0.074	View
Atovaquone 15μM R08 exp451	0.069	View
5-Fluorouracil 20μM R00 exp2	0.067	View
CI-1040 9.5μM R08 exp472	0.066	View
AICAR 240μM R03 exp116	0.063	View
5-Azacytidine 2μM R07 exp330	0.061	View
CB-5083 0.4μM R08 exp468	0.057	View
Actinomycin-D 0.001μM R00 exp3	0.056	View
Ammonium tetrathiomolybdate 10μM R08 exp448	0.055	View

GO Term	Fold Change	Genes
regulation of G2/M transition of mitotic cell cycle	26.01	ZNF830,CDK2,AURKB,BRCA1
negative regulation of mitotic cell cycle phase transition	23.75	ZNF830,CDK2,AURKB,CDC73,BCL2,BRCA1
regulation of cell cycle G2/M phase transition	23.17	ZNF830,CDK2,AURKB,BRCA1
mitotic cell cycle checkpoint signaling	20.89	ZNF830,CDK2,AURKB,BRCA1
negative regulation of mitotic cell cycle	18.47	ZNF830,CDK2,AURKB,CDC73,BCL2,BRCA1
negative regulation of cell cycle phase transition	17.46	ZNF830,CDK2,AURKB,CDC73,BCL2,BRCA1
protein-RNA complex assembly	17.13	SNU13,DDX23,RPS28,CDC73,PSIP1
negative regulation of cell cycle process	17.03	ZNF830,CDK2,AURKB,CDC73,ESPL1,BCL2,BRCA1
protein-RNA complex organization	16.34	SNU13,DDX23,RPS28,CDC73,PSIP1
regulation of mitotic cell cycle phase transition	15.78	ZNF830,CDK2,AURKB,DDX3X,CDC73,ESPL1,BCL2,BRCA1
negative regulation of cell cycle	13.01	ZNF830,CDK2,AURKB,CDC73,ESPL1,BCL2,BRCA1
regulation of cell cycle phase transition	12.26	ZNF830,CDK2,AURKB,DDX3X,CDC73,ESPL1,BCL2,BRCA1
regulation of mitotic cell cycle	10.49	ZNF830,CDK2,AURKB,DDX3X,CDC73,ESPL1,BCL2,BRCA1
ribonucleoprotein complex biogenesis	10.40	NSUN5,SNU13,DDX23,RPS28,DDX3X,CDC73,PSIP1
mRNA processing	8.83	ZNF830,SNU13,DDX23,CDC73,PSIP1,SRSF3
regulation of cell cycle process	7.36	ZNF830,CDK2,AURKB,DDX3X,CDC73,ESPL1,BCL2,BRCA1
RNA processing	6.90	NSUN5,ZNF830,SNU13,DDX23,RPS28,DDX3X,CDC73,PSIP1,SRSF3

GO Term	Fold Change	Genes
apoptosome	552.30	APAF1,CASP9
activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c	331.38	APAF1,CASP9,CYCS
Bcl-2 family protein complex	184.10	BAK1,PMAIP1,BCL2L11
thymocyte apoptotic process	165.69	BAK1,TP53,BCL2L11
positive regulation of release of cytochrome c from mitochondria	92.05	BAK1,PMAIP1,TP53,BCL2L11
positive regulation of mitochondrial membrane permeability	78.90	BAK1,VDAC2,TP53,BCL2L11
positive regulation of membrane permeability	71.26	BAK1,VDAC2,TP53,BCL2L11
regulation of mitochondrial membrane permeability	50.21	BAK1,VDAC2,PMAIP1,TP53,BCL2L11
regulation of release of cytochrome c from mitochondria	50.21	BAK1,PMAIP1,TP53,BCL2L11
apoptotic mitochondrial changes	49.31	BAK1,VDAC2,PMAIP1,TP53,BCL2L11
leukocyte apoptotic process	49.09	BAK1,CASP9,TP53,BCL2L11
regulation of membrane permeability	41.22	BAK1,VDAC2,PMAIP1,TP53,BCL2L11
positive regulation of mitochondrion organization	37.83	BAK1,MARCHF5,PMAIP1,TP53,BCL2L11
mitochondrial membrane organization	26.30	BAK1,VDAC2,PMAIP1,TP53,BCL2L11
intrinsic apoptotic signaling pathway	24.16	BAK1,APAF1,CASP9,CYCS,PMAIP1,TP53,BCL2L11
positive regulation of cysteine-type endopeptidase activity	22.45	BAK1,APAF1,CASP9,CYCS,PMAIP1
apoptotic signaling pathway	14.35	BAK1,APAF1,CASP9,CYCS,VDAC2,PMAIP1,TP53,BCL2L11
mitochondrial membrane	9.40	BAK1,HCCS,MARCHF5,ALAS1,CYCS,VDAC2,PMAIP1,COX7B,BCL2L11,FECH,MRPS5,TMEM126A
mitochondrial envelope	8.83	BAK1,HCCS,MARCHF5,ALAS1,CYCS,VDAC2,PMAIP1,COX7B,BCL2L11,FECH,MRPS5,TMEM126A

CR131-b 0.005μM R08 exp474

Mechanism of Action

Technical Notes

Compound References

Compound Supplier

Compound Characterization

Dose Response Curve

Screen Summary

Screen Results