Custirsen

Identification

Generic Name

Custirsen

DrugBank Accession Number

DB05487

Background

Custirsen is a benzopyran with potential antineoplastic activity. Custirsen acts as a selective estrogen receptor modulator (SERM), inhibiting the proliferation of estrogen-sensitive breast cancer cells. This agent also inhibits growth and induces apoptosis of glioblastoma cells via a mechanism independent of estrogen receptor-related mechanisms. Custirsen is also being investigated in the treatment of primary brain tumors.

Type

Small Molecule

Groups

Investigational

Structure

Similar Structures

Weight: Average: 7346.14
Monoisotopic: 7340.992685578
Chemical Formula: C₂₃₁H₃₁₂N₇₈O₁₁₉P₂₀S₂₀

Synonyms

Custirsen

External IDs

CC-8490
OGX-011

Pharmacology

Indication

Investigated for use/treatment in brain cancer and breast cancer.

Reduce drug development failure rates

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Contraindications & Blackbox Warnings

Avoid life-threatening adverse drug events

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Pharmacodynamics

CC-8490, a new anti-cancer compound from Celgene's proprietary class of benzopyrans, being evaluated as a potential therapy for brain cancer. The National Cancer Institute also reports applications in breast cancer related to potential antineoplastic activity. CC-8490 acts as a selective estrogen receptor modulator (SERM), inhibiting the proliferation of estrogen-sensitive breast cancer cells. This agent also inhibits growth and induces apoptosis of glioblastoma cells via a mechanism independent of estrogen receptor-related mechanisms.

Mechanism of action

CC-8490 acts as a selective estrogen receptor modulator (SERM), inhibiting the proliferation of estrogen-sensitive breast cancer cells. This agent also inhibits growth and induces apoptosis of glioblastoma cells via a mechanism independent of estrogen receptor-related mechanisms.

Preliminary results in studies regarding the mechanism of action in brain cancer suggest that C-8490 surpresses nuclear factor (NF)-KB with its target genes IEX-3, SOD2, IL6, and IL8.

Target	Actions	Organism
UEstrogen receptor alpha	Not Available	Humans
UNuclear factor NF-kappa-B p100 subunit	Not Available	Humans
UNuclear factor NF-kappa-B p105 subunit	Not Available	Humans

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Not Available

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects

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Toxicity

safe and well tolerated in a Phase I trial in healthy human volunteers.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: Not Available

Chemical Identifiers

UNII: L26E95NLRK
CAS number: 890056-27-6
InChI Key: RCFZILUHCNXXFY-DEDWCYLFSA-N
InChI: InChI=1S/C231H312N78O119P20S20/c1-97-52-295(224(324)273-181(97)235)210-174(361-32-24-353-10)166(118(60-310)401-210)422-444(347,464)383-78-136-171(179(366-37-29-358-15)215(406-136)308-95-265-160-189(243)253-86-259-195(160)308)427-448(351,468)387-80-138-172(180(367-38-30-359-16)216(408-138)309-96-269-164-199(309)279-220(247)283-208(164)320)428-447(350,467)385-76-134-168(175(362-33-25-354-11)211(403-134)296-53-98(2)182(236)274-225(296)325)423-442(345,462)380-73-131-114(48-151(397-131)303-90-263-158-187(241)251-84-257-193(158)303)417-439(342,459)379-72-128-115(49-152(398-128)304-91-266-161-196(304)276-217(244)280-205(161)317)418-435(338,455)370-63-121-107(41-144(390-121)291-22-19-141(234)272-223(291)323)411-430(333,450)374-67-125-111(45-148(394-125)300-87-260-155-184(238)248-81-254-190(155)300)415-437(340,457)378-71-130-117(51-154(400-130)306-93-268-163-198(306)278-219(246)282-207(163)319)420-440(343,460)376-68-126-112(46-149(395-126)301-88-261-156-185(239)249-82-255-191(156)301)416-438(341,458)377-70-129-116(50-153(399-129)305-92-267-162-197(305)277-218(245)281-206(162)318)419-436(339,456)373-66-124-109(43-146(393-124)293-56-101(5)201(313)285-228(293)328)413-433(336,453)368-61-119-105(39-142(388-119)289-20-17-139(232)270-221(289)321)409-429(332,449)371-64-122-110(44-147(391-122)294-57-102(6)202(314)286-229(294)329)414-434(337,454)372-65-123-108(42-145(392-123)292-55-100(4)200(312)284-227(292)327)412-432(335,452)369-62-120-106(40-143(389-120)290-21-18-140(233)271-222(290)322)410-431(334,451)375-69-127-113(47-150(396-127)302-89-262-157-186(240)250-83-256-192(157)302)421-441(344,461)382-75-133-167(177(364-35-27-356-13)213(405-133)299-59-104(8)204(316)288-231(299)331)424-445(348,465)384-77-135-169(176(363-34-26-355-12)212(404-135)297-54-99(3)183(237)275-226(297)326)425-446(349,466)386-79-137-170(178(365-36-28-357-14)214(407-137)307-94-264-159-188(242)252-85-258-194(159)307)426-443(346,463)381-74-132-165(311)173(360-31-23-352-9)209(402-132)298-58-103(7)203(315)287-230(298)330/h17-22,52-59,81-96,105-138,142-154,165-180,209-216,310-311H,23-51,60-80H2,1-16H3,(H,332,449)(H,333,450)(H,334,451)(H,335,452)(H,336,453)(H,337,454)(H,338,455)(H,339,456)(H,340,457)(H,341,458)(H,342,459)(H,343,460)(H,344,461)(H,345,462)(H,346,463)(H,347,464)(H,348,465)(H,349,466)(H,350,467)(H,351,468)(H2,232,270,321)(H2,233,271,322)(H2,234,272,323)(H2,235,273,324)(H2,236,274,325)(H2,237,275,326)(H2,238,248,254)(H2,239,249,255)(H2,240,250,256)(H2,241,251,257)(H2,242,252,258)(H2,243,253,259)(H,284,312,327)(H,285,313,328)(H,286,314,329)(H,287,315,330)(H,288,316,331)(H3,244,276,280,317)(H3,245,277,281,318)(H3,246,278,282,319)(H3,247,279,283,320)/t105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118+,119+,120+,121+,122+,123+,124+,125+,126+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,142+,143+,144+,145+,146+,147+,148+,149+,150+,151+,152+,153+,154+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,178+,179+,180+,209+,210+,211+,212+,213+,214+,215+,216+,429?,430?,431?,432?,433?,434?,435?,436?,437?,438?,439?,440?,441?,442?,443?,444?,445?,446?,447?,448?/m0/s1
IUPAC Name: (2R,3R,4R,5R)-2-{[({[(2R,3R,4R,5R)-2-{[({[(2R,3R,4R,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3S,5R)-2-{[({[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-{[({[(2R,3R,4R,5R)-2-{[({[(2R,3R,4R,5R)-2-{[({[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-2-(hydroxymethyl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy}(sulfanyl)phosphoryl)oxy]methyl}-5-(6-amino-9H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl [(2R,3R,4R,5R)-3-hydroxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-2-yl]methyl sulfanylphosphonate
SMILES: COCCO[C@@H]1[C@H](O)[C@@H](COP(S)(=O)O[C@@H]2[C@@H](COP(S)(=O)O[C@@H]3[C@@H](COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@H]5C[C@@H](O[C@@H]5COP(S)(=O)O[C@@H]5[C@@H](COP(S)(=O)O[C@@H]6[C@@H](COP(S)(=O)O[C@@H]7[C@@H](COP(S)(=O)O[C@@H]8[C@@H](CO)O[C@H]([C@@H]8OCCOC)N8C=C(C)C(N)=NC8=O)O[C@H]([C@@H]7OCCOC)N7C=NC8=C7N=CN=C8N)O[C@H]([C@@H]6OCCOC)N6C=NC7=C6N=C(N)NC7=O)O[C@H]([C@@H]5OCCOC)N5C=C(C)C(N)=NC5=O)N5C=NC6=C5N=CN=C6N)N5C=NC6=C5N=C(N)NC6=O)N5C=CC(N)=NC5=O)N5C=NC6=C5N=CN=C6N)N5C=NC6=C5N=C(N)NC6=O)N5C=NC6=C5N=CN=C6N)N5C=NC6=C5N=C(N)NC6=O)N5C=C(C)C(=O)NC5=O)N5C=CC(N)=NC5=O)N5C=C(C)C(=O)NC5=O)N5C=C(C)C(=O)NC5=O)N5C=CC(N)=NC5=O)N5C=NC6=C5N=CN=C6N)O[C@H]([C@@H]4OCCOC)N4C=C(C)C(=O)NC4=O)O[C@H]([C@@H]3OCCOC)N3C=C(C)C(N)=NC3=O)O[C@H]([C@@H]2OCCOC)N2C=NC3=C2N=CN=C3N)O[C@H]1N1C=C(C)C(=O)NC1=O

References

General References

Hui AM, Zhang W, Chen W, Xi D, Purow B, Friedman GC, Fine HA: Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells. Cancer Res. 2004 Dec 15;64(24):9115-23. [Article]

External Links

PubChem Substance: 347910168
ChemSpider: 34983386
Wikipedia: Custirsen

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Prostate Cancer	2
3	Terminated	Treatment	Castration Resistant Prostate Cancer / Hormone Refractory Prostate Cancer	1
3	Unknown Status	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	1
2	Completed	Treatment	Breast Cancer	1
2	Completed	Treatment	Prostate Cancer	3
1	Completed	Not Available	Cancer	1
1	Completed	Treatment	Bladder Cancer, Cancer / Breast Cancer / Lung Cancers / Ovarian Cancer / Prostate Cancer / Renal Cancers / Unspecified Adult Solid Tumor, Protocol Specific	1
1	Completed	Treatment	Brain and Central Nervous System Tumors	1
1	Completed	Treatment	Cardiac Conduction and Repolarization	1
1	Completed	Treatment	Glioblastoma Multiforme (GBM) / Gliomas, Malignant	1

Pharmacoeconomics

Manufacturers: Not Available
Packagers: Not Available
Dosage Forms: Not Available
Prices: Not Available
Patents: Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
logP	-2.2	ChemAxon
pKa (Strongest Acidic)	0.066	ChemAxon
Physiological Charge	-10	ChemAxon
Hydrogen Acceptor Count	127	ChemAxon
Hydrogen Donor Count	47	ChemAxon
Polar Surface Area	2450.68 Å²	ChemAxon
Rotatable Bond Count	154	ChemAxon
Refractivity	1591.03 m³·mol^-1	ChemAxon
Polarizability	653.99 Å³	ChemAxon
Number of Rings	52	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST): Not Available
Spectra: Not Available

Targets

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Details1. Estrogen receptor alpha

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Zinc ion binding
Specific Function: Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...
Gene Name: ESR1
Uniprot ID: P03372
Uniprot Name: Estrogen receptor
Molecular Weight: 66215.45 Da

Details2. Nuclear factor NF-kappa-B p100 subunit

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Transcriptional activator activity, rna polymerase ii core promoter proximal region sequence-specific binding
Specific Function: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related...
Gene Name: NFKB2
Uniprot ID: Q00653
Uniprot Name: Nuclear factor NF-kappa-B p100 subunit
Molecular Weight: 96748.355 Da

Details3. Nuclear factor NF-kappa-B p105 subunit

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Transcriptional repressor activity, rna polymerase ii transcription regulatory region sequence-specific binding
Specific Function: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related...
Gene Name: NFKB1
Uniprot ID: P19838
Uniprot Name: Nuclear factor NF-kappa-B p105 subunit
Molecular Weight: 105355.175 Da

Drug created at November 18, 2007 18:25 / Updated at February 21, 2021 18:51

Custirsen

Identification

Structure for Custirsen (DB05487)

Pharmacology

Interactions

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets