|
Apparent inhibition constant for estrogen receptor in Human Breast cancer cytosol in 2.5%DMF
|
Homo sapiens
|
0.755
nM
|
|
Journal : J. Med. Chem.
Title : (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen.
Year : 1997
Volume : 40
Issue : 14
First Page : 2117
Last Page : 2122
Authors : Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Mérand Y, Bélanger A, Labrie C, Labrie F.
|
Inhibition of estradiol binding to estrogen receptor in Human Breast cancer cytosol (3.3% ethanol)
|
Homo sapiens
|
7.63
nM
|
|
Journal : J. Med. Chem.
Title : (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen.
Year : 1997
Volume : 40
Issue : 14
First Page : 2117
Last Page : 2122
Authors : Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Mérand Y, Bélanger A, Labrie C, Labrie F.
|
Apparent inhibition constant for estrogen receptor in Human uterine cytosol in 2.5%DMF
|
Homo sapiens
|
0.668
nM
|
|
Journal : J. Med. Chem.
Title : (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen.
Year : 1997
Volume : 40
Issue : 14
First Page : 2117
Last Page : 2122
Authors : Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Mérand Y, Bélanger A, Labrie C, Labrie F.
|
In vitro displacement of 0.5 nM [3H]17-beta-estradiol from human Estrogen receptor alpha
|
Homo sapiens
|
1.04
nM
|
|
Journal : J. Med. Chem.
Title : De novo design, synthesis, and evaluation of novel nonsteroidal phenanthrene ligands for the estrogen receptor.
Year : 2003
Volume : 46
Issue : 8
First Page : 1408
Last Page : 1418
Authors : Schmidt JM, Mercure J, Tremblay GB, Pagé M, Kalbakji A, Feher M, Dunn-Dufault R, Peter MG, Redden PR.
Abstract : Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. Here, we describe the discovery of a novel phenanthrene scaffold for estrogen receptor ligands utilizing a ligand based de novo design approach. The nanomolar binding of phenanthrenes, 12b,c, 14b,c, and 15 against human recombinant ER(alpha) indicates that our ligand based de novo design approach was successful. From a gene transfection assay, 12b,c, 14b,c, and 15 displayed only antagonistic activity with no observable agonistic activity. The alkyl 9,10-dihydrophenanthrene 16 (presumably a racemic mixture) was a substantially more potent ER binder than the phenanthrenes. It also displayed only antagonistic activity and was effective at inhibiting estradiol stimulated MCF-7 cell proliferation. These results demonstrate that this phenanthrene (and 9,10-dihydrophenanthrene) scaffold warrants further study as potential selective estrogen receptor modulators and/or pure antiestrogens.
|
In vitro displacement of 0.5 nM [3H]17-beta-estradiol from human Estrogen receptor beta
|
Homo sapiens
|
1.39
nM
|
|
Journal : J. Med. Chem.
Title : De novo design, synthesis, and evaluation of novel nonsteroidal phenanthrene ligands for the estrogen receptor.
Year : 2003
Volume : 46
Issue : 8
First Page : 1408
Last Page : 1418
Authors : Schmidt JM, Mercure J, Tremblay GB, Pagé M, Kalbakji A, Feher M, Dunn-Dufault R, Peter MG, Redden PR.
Abstract : Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. Here, we describe the discovery of a novel phenanthrene scaffold for estrogen receptor ligands utilizing a ligand based de novo design approach. The nanomolar binding of phenanthrenes, 12b,c, 14b,c, and 15 against human recombinant ER(alpha) indicates that our ligand based de novo design approach was successful. From a gene transfection assay, 12b,c, 14b,c, and 15 displayed only antagonistic activity with no observable agonistic activity. The alkyl 9,10-dihydrophenanthrene 16 (presumably a racemic mixture) was a substantially more potent ER binder than the phenanthrenes. It also displayed only antagonistic activity and was effective at inhibiting estradiol stimulated MCF-7 cell proliferation. These results demonstrate that this phenanthrene (and 9,10-dihydrophenanthrene) scaffold warrants further study as potential selective estrogen receptor modulators and/or pure antiestrogens.
|
Displacement of [3H]17-beta-estradiol from human Estrogen receptor alpha
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and estrogenic activities of novel 7-thiosubstituted estratriene derivatives.
Year : 2000
Volume : 10
Issue : 2
First Page : 147
Last Page : 151
Authors : Miller CP, Jirkovsky I, Tran BD, Harris HA, Moran RA, Komm BS.
Abstract : A diastereomerically pure series of 7alpha-thioestratrienes was prepared and evaluated for its affinity for both the human estrogen receptor alpha and the more recently discovered estrogen receptor beta. The functional estrogenic activities of the compounds were measured in a MCF-7 ERE-tk-luciferase assay. The activities and selectivities of the compounds were sensitive to the nature of the thioether side chain.
|
Antagonist effect on transcriptional activation in MCF-7 cells expressing estrogen receptor alpha
|
Homo sapiens
|
0.47
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and estrogenic activities of novel 7-thiosubstituted estratriene derivatives.
Year : 2000
Volume : 10
Issue : 2
First Page : 147
Last Page : 151
Authors : Miller CP, Jirkovsky I, Tran BD, Harris HA, Moran RA, Komm BS.
Abstract : A diastereomerically pure series of 7alpha-thioestratrienes was prepared and evaluated for its affinity for both the human estrogen receptor alpha and the more recently discovered estrogen receptor beta. The functional estrogenic activities of the compounds were measured in a MCF-7 ERE-tk-luciferase assay. The activities and selectivities of the compounds were sensitive to the nature of the thioether side chain.
|
Displacement of [3H]17-beta-estradiol from human Estrogen receptor beta
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and estrogenic activities of novel 7-thiosubstituted estratriene derivatives.
Year : 2000
Volume : 10
Issue : 2
First Page : 147
Last Page : 151
Authors : Miller CP, Jirkovsky I, Tran BD, Harris HA, Moran RA, Komm BS.
Abstract : A diastereomerically pure series of 7alpha-thioestratrienes was prepared and evaluated for its affinity for both the human estrogen receptor alpha and the more recently discovered estrogen receptor beta. The functional estrogenic activities of the compounds were measured in a MCF-7 ERE-tk-luciferase assay. The activities and selectivities of the compounds were sensitive to the nature of the thioether side chain.
|
Inhibition of estrogen-induced proliferation in human MCF-7 breast cancer cells
|
Homo sapiens
|
0.49
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene: a novel, highly potent, selective estrogen receptor modulator.
Year : 1997
Volume : 40
Issue : 10
First Page : 1407
Last Page : 1416
Authors : Palkowitz AD, Glasebrook AL, Thrasher KJ, Hauser KL, Short LL, Phillips DL, Muehl BS, Sato M, Shetler PK, Cullinan GJ, Pell TR, Bryant HU.
Abstract : Raloxifene,[2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (2), is representative of a class of compounds known as selective estrogen receptor modulators (SERMs) that possess estrogen agonist-like actions on bone tissues and serum lipids while displaying potent estrogen antagonist properties in the breast and uterus. As part of ongoing SAR studies with raloxifene, we found that replacement of the carbonyl group with oxygen ([6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene hydrochloride, 4c) resulted in a substantial (10-fold) increase in estrogen antagonist potency relative to raloxifene in an in vitro estrogen dependent cell proliferation assay (IC50 = 0.05 nM) in which human breast cancer cells (MCF-7) were utilized. In vivo, 4c potently inhibited the uterine proliferative response to exogenous estrogen in immature rats following both sc and oral dosing (ED50 of 0.006 and 0.25 mg/kg, respectively). In ovariectomized aged rats, 4c produced a significant maximal decrease (45%) in total cholesterol at 1.0 mg/kg (p.o.) and showed a protective effect on bone relative to controls with maximal efficacy at 1.0 mg/kg (p.o.). These data identify 4c as a novel SERM with greater potency to antagonize estrogen in uterine tissue and in human mammary cancer cells compared to raloxifene, tamoxifen or ICI-182,780.
|
Antagonist effect as ability to suppress uterine stimulatory EE2 effect in immature female rats at 0.1 mg/kg dose
|
Rattus norvegicus
|
40.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : B-ring unsaturated estrogens: biological evaluation of 17alpha-Dihydroequilein and novel B-Nor-6-thiaequilenins as tissue selective estrogens.
Year : 2003
Volume : 13
Issue : 24
First Page : 4281
Last Page : 4284
Authors : Lugar CW, Magee D, Adrian MD, Shetler P, Bryant HU, Dodge JA.
Abstract : The pharmacology and SAR of representative equine estogens is described. 17alpha-Dihydroequilenin was found to prevent bone loss after 5 weeks of oral administration to ovariectomized rats. The stereochemical significance of the D-ring and the C/D ring juncture was investigated with a series of benzothiophene-based equilenin analogues.
|
Antagonist effect as ability to suppress uterine stimulatory EE2 effect in immature female rats at 1.0 mg/kg dose
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : B-ring unsaturated estrogens: biological evaluation of 17alpha-Dihydroequilein and novel B-Nor-6-thiaequilenins as tissue selective estrogens.
Year : 2003
Volume : 13
Issue : 24
First Page : 4281
Last Page : 4284
Authors : Lugar CW, Magee D, Adrian MD, Shetler P, Bryant HU, Dodge JA.
Abstract : The pharmacology and SAR of representative equine estogens is described. 17alpha-Dihydroequilenin was found to prevent bone loss after 5 weeks of oral administration to ovariectomized rats. The stereochemical significance of the D-ring and the C/D ring juncture was investigated with a series of benzothiophene-based equilenin analogues.
|
Antagonist effect as ability to suppress uterine stimulatory EE2 effect in immature female rats at 10.0 mg/kg dose
|
Rattus norvegicus
|
117.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : B-ring unsaturated estrogens: biological evaluation of 17alpha-Dihydroequilein and novel B-Nor-6-thiaequilenins as tissue selective estrogens.
Year : 2003
Volume : 13
Issue : 24
First Page : 4281
Last Page : 4284
Authors : Lugar CW, Magee D, Adrian MD, Shetler P, Bryant HU, Dodge JA.
Abstract : The pharmacology and SAR of representative equine estogens is described. 17alpha-Dihydroequilenin was found to prevent bone loss after 5 weeks of oral administration to ovariectomized rats. The stereochemical significance of the D-ring and the C/D ring juncture was investigated with a series of benzothiophene-based equilenin analogues.
|
Inhibition of human estrogen receptor 2 using tritiated estradiol incubated for 3 hr
|
Homo sapiens
|
8.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 13: Dihydrobenzoxathiin SERAMs with an optimized antagonist side chain.
Year : 2005
Volume : 15
Issue : 17
First Page : 3912
Last Page : 3916
Authors : Blizzard TA, DiNinno F, Chen HY, Kim S, Wu JY, Chan W, Birzin ET, Yang YT, Pai LY, Hayes EC, DaSilva CA, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
|
Inhibition of ER-MDA-MB 231 breast cancer cell proliferation over 200 hr
|
Homo sapiens
|
0.21
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of stilbene-based pure estrogen antagonists.
Year : 2004
Volume : 14
Issue : 18
First Page : 4659
Last Page : 4663
Authors : Walter G, Liebl R, von Angerer E.
Abstract : Replacement of one of the ethyl substituents in diethylstilbestrol by side chains with functional groups converted this potent estrogen into pure antiestrogens with the potential for the treatment of breast cancer. These agents completely suppressed estrogen receptor-mediated gene activation and inhibited the growth of estrogen-sensitive MCF-7 breast cancer cells in submicromolar concentrations. The most potent derivative displayed similar activity as fulvestrant (ICI 182,780) in vitro and in the mouse uterine weight test. Obviously, the stilbene structure can act as a substitute for estradiol in the development of pure estrogen antagonists.
|
Inhibition of 10e-9 M E2 stimulated MCF-7 breast cancer cell proliferation
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of stilbene-based pure estrogen antagonists.
Year : 2004
Volume : 14
Issue : 18
First Page : 4659
Last Page : 4663
Authors : Walter G, Liebl R, von Angerer E.
Abstract : Replacement of one of the ethyl substituents in diethylstilbestrol by side chains with functional groups converted this potent estrogen into pure antiestrogens with the potential for the treatment of breast cancer. These agents completely suppressed estrogen receptor-mediated gene activation and inhibited the growth of estrogen-sensitive MCF-7 breast cancer cells in submicromolar concentrations. The most potent derivative displayed similar activity as fulvestrant (ICI 182,780) in vitro and in the mouse uterine weight test. Obviously, the stilbene structure can act as a substitute for estradiol in the development of pure estrogen antagonists.
|
Inhibition of 10e-9 M E2 stimulated transcriptional activation in ER+MCF-7/2a breast cancer cells
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of stilbene-based pure estrogen antagonists.
Year : 2004
Volume : 14
Issue : 18
First Page : 4659
Last Page : 4663
Authors : Walter G, Liebl R, von Angerer E.
Abstract : Replacement of one of the ethyl substituents in diethylstilbestrol by side chains with functional groups converted this potent estrogen into pure antiestrogens with the potential for the treatment of breast cancer. These agents completely suppressed estrogen receptor-mediated gene activation and inhibited the growth of estrogen-sensitive MCF-7 breast cancer cells in submicromolar concentrations. The most potent derivative displayed similar activity as fulvestrant (ICI 182,780) in vitro and in the mouse uterine weight test. Obviously, the stilbene structure can act as a substitute for estradiol in the development of pure estrogen antagonists.
|
Antagonist activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 10 mg/kg, sc
|
Mus musculus
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 15
First Page : 4090
Last Page : 4094
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Tsunenari T, Taniguchi K, Ohizumi I, Kaiho S, Nabuchi Y, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
|
Antagonist activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 10 mg/kg, po
|
Mus musculus
|
54.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 15
First Page : 4090
Last Page : 4094
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Tsunenari T, Taniguchi K, Ohizumi I, Kaiho S, Nabuchi Y, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
|
Antagonist activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 50 mg/kg, po
|
Mus musculus
|
86.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 15
First Page : 4090
Last Page : 4094
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Tsunenari T, Taniguchi K, Ohizumi I, Kaiho S, Nabuchi Y, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
|
Antagonist activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 30 mg/kg, po
|
Mus musculus
|
72.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 15
First Page : 4090
Last Page : 4094
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Tsunenari T, Taniguchi K, Ohizumi I, Kaiho S, Nabuchi Y, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
|
Antagonist activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 3 mg/kg, po
|
Mus musculus
|
29.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 15
First Page : 4090
Last Page : 4094
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Tsunenari T, Taniguchi K, Ohizumi I, Kaiho S, Nabuchi Y, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.
|
Antagonist effect on estrogen activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 1 mg/kg, po
|
Mus musculus
|
11.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Newly discovered orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 18
First Page : 4959
Last Page : 4964
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Yoneya T, Ohizumi I, Tsunenari T, Taniguchi K, Kaiho S, Nabuchi Y, Araya H, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.
|
Antagonist effect on estrogen activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 3 mg/kg, po
|
Mus musculus
|
29.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Newly discovered orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 18
First Page : 4959
Last Page : 4964
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Yoneya T, Ohizumi I, Tsunenari T, Taniguchi K, Kaiho S, Nabuchi Y, Araya H, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.
|
Antagonist effect on estrogen activity assessed as inhibition of estrogen-stimulated uterine weight gain in ovariectomized mouse at 10 mg/kg, po
|
Mus musculus
|
54.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Newly discovered orally active pure antiestrogens.
Year : 2006
Volume : 16
Issue : 18
First Page : 4959
Last Page : 4964
Authors : Kanbe Y, Kim MH, Nishimoto M, Ohtake Y, Yoneya T, Ohizumi I, Tsunenari T, Taniguchi K, Kaiho S, Nabuchi Y, Araya H, Kawata S, Morikawa K, Jo JC, Kwon HA, Lim HS, Kim HY.
Abstract : In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.
|
Binding affinity to human ERalpha
|
Homo sapiens
|
4.9
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons.
Year : 2007
Volume : 50
Issue : 18
First Page : 4471
Last Page : 4481
Authors : Zhao L, Jin C, Mao Z, Gopinathan MB, Rehder K, Brinton RD.
Abstract : We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7alpha-[(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17beta-diol (2), a hybrid structure of 17beta-estradiol and vitamin E, was synthesized and found to bind to both ERalpha and ERbeta. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain-selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women.
|
Binding affinity to human ERbeta
|
Homo sapiens
|
44.1
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons.
Year : 2007
Volume : 50
Issue : 18
First Page : 4471
Last Page : 4481
Authors : Zhao L, Jin C, Mao Z, Gopinathan MB, Rehder K, Brinton RD.
Abstract : We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7alpha-[(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17beta-diol (2), a hybrid structure of 17beta-estradiol and vitamin E, was synthesized and found to bind to both ERalpha and ERbeta. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain-selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women.
|
Cytotoxicity against human LNCAP cells after 4 days by MTT assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 9,11-Secosterols with antiproliferative activity from the gorgonian Eunicella cavolini.
Year : 2009
Volume : 17
Issue : 13
First Page : 4537
Last Page : 4541
Authors : Ioannou E, Abdel-Razik AF, Alexi X, Vagias C, Alexis MN, Roussis V.
Abstract : Four new 9,11-secosterols (2, 4-6), along with two previously reported ones (1, 3) were isolated from the organic extract of the gorgonian Eunicella cavolini. The structures and relative configurations of the isolated natural products were established on the basis of detailed NMR spectroscopic analysis. Metabolites 1 and 2 were found to strongly inhibit the growth of LNCaP human prostate adenocarcinoma cells and the estrogen-dependent growth of MCF-7 human breast adenocarcinoma cells.
|
Cytotoxicity against human MCF7 cells after 4 days by MTT assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 9,11-Secosterols with antiproliferative activity from the gorgonian Eunicella cavolini.
Year : 2009
Volume : 17
Issue : 13
First Page : 4537
Last Page : 4541
Authors : Ioannou E, Abdel-Razik AF, Alexi X, Vagias C, Alexis MN, Roussis V.
Abstract : Four new 9,11-secosterols (2, 4-6), along with two previously reported ones (1, 3) were isolated from the organic extract of the gorgonian Eunicella cavolini. The structures and relative configurations of the isolated natural products were established on the basis of detailed NMR spectroscopic analysis. Metabolites 1 and 2 were found to strongly inhibit the growth of LNCaP human prostate adenocarcinoma cells and the estrogen-dependent growth of MCF-7 human breast adenocarcinoma cells.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 3 uM after 7 hrs
|
Homo sapiens
|
15.7
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Antagonist activity at estrogen receptor alpha ligand binding domain expressed in african green monkey COS7 cells co-transfected with Gal4-LBD by luciferase reporter gene assay
|
None
|
4.0
nM
|
|
Journal : J. Nat. Prod.
Title : The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144.
Year : 2009
Volume : 72
Issue : 11
First Page : 1944
Last Page : 1948
Authors : Roll DM, Barbieri LR, Bigelis R, McDonald LA, Arias DA, Chang LP, Singh MP, Luckman SW, Berrodin TJ, Yudt MR.
Abstract : Four new indolosesquiterpenes, lecanindoles A-D (1-4), were isolated from fermentations of the terrestrial fungus Verticillium lecanii 6144. The structures of compounds 1-4 were elucidated from analysis of spectroscopic data. Compound 2 was reduced to give 4 and its isomer 5. Compound 4 was found to be a potent and selective progesterone receptor agonist with an EC50 of 1.1 +/- 0.4 nM in a cell-based luciferase reporter assay.
|
Antagonist activity at estrogen receptor beta ligand binding domain expressed in african green monkey COS7 cells co-transfected with Gal4-LBD by luciferase reporter gene assay
|
None
|
3.8
nM
|
|
Journal : J. Nat. Prod.
Title : The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144.
Year : 2009
Volume : 72
Issue : 11
First Page : 1944
Last Page : 1948
Authors : Roll DM, Barbieri LR, Bigelis R, McDonald LA, Arias DA, Chang LP, Singh MP, Luckman SW, Berrodin TJ, Yudt MR.
Abstract : Four new indolosesquiterpenes, lecanindoles A-D (1-4), were isolated from fermentations of the terrestrial fungus Verticillium lecanii 6144. The structures of compounds 1-4 were elucidated from analysis of spectroscopic data. Compound 2 was reduced to give 4 and its isomer 5. Compound 4 was found to be a potent and selective progesterone receptor agonist with an EC50 of 1.1 +/- 0.4 nM in a cell-based luciferase reporter assay.
|
Inhibition of CETP in rabbit serum at 10 uM after 1 hr by fluorescent cholesteryl esters transfer assay
|
Oryctolagus cuniculus
|
5.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration.
Year : 2010
Volume : 45
Issue : 4
First Page : 1598
Last Page : 1617
Authors : Abu Khalaf R, Abu Sheikha G, Bustanji Y, Taha MO.
Abstract : Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) against 22 external test inhibitors=0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles. The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 (IC(50)=1.9 microM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.
|
Displacement of [3H]estradiol from rat uterine cytosolic estrogen receptor
|
Rattus norvegicus
|
5.888
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 2-Morpholinoisoflav-3-enes as flexible intermediates in the synthesis of phenoxodiol, isophenoxodiol, equol and analogues: vasorelaxant properties, estrogen receptor binding and Rho/RhoA kinase pathway inhibition.
Year : 2012
Volume : 20
Issue : 7
First Page : 2353
Last Page : 2361
Authors : Tilley AJ, Zanatta SD, Qin CX, Kim IK, Seok YM, Stewart A, Woodman OL, Williams SJ.
Abstract : Isoflavone consumption correlates with reduced rates of cardiovascular disease. Epidemiological studies and clinical data provide evidence that isoflavone metabolites, such as the isoflavan equol, contribute to these beneficial effects. In this study we developed a new route to isoflavans and isoflavenes via 2-morpholinoisoflavenes derived from a condensation reaction of phenylacetaldehydes, salicylaldehydes and morpholine. We report the synthesis of the isoflavans equol and deoxygenated analogues, and the isoflavenes 7,4'-dihydroxyisoflav-3-ene (phenoxodiol, haganin E) and 7,4'-dihydroxyisoflav-2-ene (isophenoxodiol). Vascular pharmacology studies reveal that all oxygenated isoflavans and isoflavenes can attenuate phenylephrine-induced vasoconstriction, which was unaffected by the estrogen receptor antagonist ICI 182,780. Furthermore, the compounds inhibited U46619 (a thromboxane A(2) analogue) induced vasoconstriction in endothelium-denuded rat aortae, and reduced the formation of GTP RhoA, with the effects being greatest for equol and phenoxodiol. Ligand displacement studies of rat uterine cytosol estrogen receptor revealed the compounds to be generally weak binders. These data are consistent with the vasorelaxation activity of equol and phenoxodiol deriving at least in part by inhibition of the RhoA/Rho-kinase pathway, and along with the limited estrogen receptor affinity supports a role for equol and phenoxodiol as useful agents for maintaining cardiovascular function with limited estrogenic effects.
|
Antagonist activity at ERalpha receptor in human MCF7 cells assessed as inhibition of cell growth after 6 days by crystal violet staining method
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity.
Year : 2013
Volume : 56
Issue : 7
First Page : 2779
Last Page : 2790
Authors : Jiang XR, Wang P, Smith CL, Zhu BT.
Abstract : Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα and showed that they could tightly bind to the ERα in a manner similar to that of ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780.
|
Antagonist activity at human GTS-tagged FXR after 20 mins by TR-FRET assay
|
Homo sapiens
|
790.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.
Year : 2013
Volume : 21
Issue : 14
First Page : 4266
Last Page : 4278
Authors : Yu DD, Lin W, Chen T, Forman BM.
Abstract : FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists.
|
Antagonist activity at human GTS-tagged FXR at 15 uM after 20 mins by TR-FRET assay
|
Homo sapiens
|
62.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.
Year : 2013
Volume : 21
Issue : 14
First Page : 4266
Last Page : 4278
Authors : Yu DD, Lin W, Chen T, Forman BM.
Abstract : FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists.
|
Competitive inhibition of human recombinant soluble epoxide hydrolase using [3H]-tDPPO as substrate
|
Homo sapiens
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides.
Year : 2013
Volume : 23
Issue : 13
First Page : 3818
Last Page : 3821
Authors : Morisseau C, Pakhomova S, Hwang SH, Newcomer ME, Hammock BD.
Abstract : The soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of epoxy-fatty acids, signaling molecules involved in numerous biologies. Toward finding novel inhibitors of sEH, a library of known drugs was tested for inhibition of sEH. We found that fulvestrant, an anticancer agent, is a potent (KI=26 nM) competitive inhibitor of sEH. From this observation, we found that alkyl-sulfoxides represent a new kind of pharmacophore for the inhibition of sEH.
|
Inhibition of human recombinant soluble epoxide hydrolase using (cyano(6-methoxy-naphthelen-2-yl)methyl trans-[(3-phenyl-oxiran-2-yl)methyl] carbonate) as substrate preincubated for 5 mins prior to substrate addition by fluorescence assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides.
Year : 2013
Volume : 23
Issue : 13
First Page : 3818
Last Page : 3821
Authors : Morisseau C, Pakhomova S, Hwang SH, Newcomer ME, Hammock BD.
Abstract : The soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of epoxy-fatty acids, signaling molecules involved in numerous biologies. Toward finding novel inhibitors of sEH, a library of known drugs was tested for inhibition of sEH. We found that fulvestrant, an anticancer agent, is a potent (KI=26 nM) competitive inhibitor of sEH. From this observation, we found that alkyl-sulfoxides represent a new kind of pharmacophore for the inhibition of sEH.
|
Inhibition of 17beta-estradiol-induced in ERalpha positive human MCF7 cells proliferation assessed as [3H]-thymidine incorporation after 72 hrs by liquid scintillation counting
|
Homo sapiens
|
1.9
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of salpichrolide analogs as antiestrogenic agents.
Year : 2014
Volume : 82
First Page : 233
Last Page : 241
Authors : Sonego JM, Rivero EM, Gargiulo L, Lüthy I, Alvarez LD, Veleiro AS, Burton G.
Abstract : The antiestrogenic activity of three natural salpichrolides A, G and B (1, 3 and 4) and of five synthetic analogs containing an aromatic D ring and a simplified side chain (5-9), was evaluated on MCF-7 cells. The 2,3-ene-1-keto steroids 8 and 9 were obtained from 3β-acetoxy-17(13→18)-abeo-5αH-pregna-13,15,17-trien-20-one, the key step for these syntheses being a Wharton carbonyl rearrangement of a 1,2-epoxy-3-keto steroid to the allylic alcohol using hydrazine hydrate. The antiestrogenic activity was evaluated by performing dose-response experiments in ER(+) MCF-7 breast cancer cells. Dose-dependent proliferation was quantified via [(3)H]-thymidine incorporation after 3 days treatment. Salpichrolides A, G and B and analogs 5, 8 and 9 were active as antiestrogens with compound 9 being the most active of the synthetic analogs. Compounds 5 and 9 were also evaluated against the ER(-) cell line MDA-MB-231 and shown to be inactive.
|
Induction of estrogen receptor-alpha degradation in human MCF7 cells after 4 hrs by in-cell western assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
Year : 2015
Volume : 58
Issue : 12
First Page : 4888
Last Page : 4904
Authors : Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
|
Cytotoxicity against human MCF7 cells assessed as cell viability after 5 days by CellTiter-Glo assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
Year : 2015
Volume : 58
Issue : 12
First Page : 4888
Last Page : 4904
Authors : Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
|
Displacement of [3H]-E2 from estrogen receptor-alpha (unknown origin) by scintillation counting analysis
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
Year : 2015
Volume : 58
Issue : 12
First Page : 4888
Last Page : 4904
Authors : Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
|
Displacement of [3H]-E2 from estrogen receptor-beta (unknown origin) by scintillation counting analysis
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
Year : 2015
Volume : 58
Issue : 12
First Page : 4888
Last Page : 4904
Authors : Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
|
Antagonist activity at estrogen receptor in human MCF7 cells assessed as inhibition of 17beta-estradiol-mediated transcriptional activation after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.
Year : 2015
Volume : 58
Issue : 12
First Page : 4888
Last Page : 4904
Authors : Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, Douglas K, Sensintaffar J, Lu N, Lee KJ, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Moon MJ, Joseph JD, Darimont B, Brigham D, Grillot K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
|
Binding affinity to ERalpha receptor (unknown origin)
|
Homo sapiens
|
0.8128
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Antagonist activity at ERalpha receptor in human MCF7 cells
|
Homo sapiens
|
0.0631
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Antagonist activity at progesterone receptor in human MCF cells assessed as estradiol-induced receptor response
|
Homo sapiens
|
0.2089
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Antiproliferative activity against human MCF7 cells
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Year : 2015
Volume : 58
Issue : 20
First Page : 8128
Last Page : 8140
Authors : De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z.
Abstract : The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
|
Decrease in estrogen receptor alpha level in human MCF7 cells after 4 hrs by in-cell western assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.
Year : 2015
Volume : 25
Issue : 22
First Page : 5163
Last Page : 5167
Authors : Govek SP, Nagasawa JY, Douglas KL, Lai AG, Kahraman M, Bonnefous C, Aparicio AM, Darimont BD, Grillot KL, Joseph JD, Kaufman JA, Lee KJ, Lu N, Moon MJ, Prudente RY, Sensintaffar J, Rix PJ, Hager JH, Smith ND.
Abstract : Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
|
Cytotoxicity against human MCF7 cells assessed as decrease in cell viability after 5 days by celltiterGlo assay
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.
Year : 2015
Volume : 25
Issue : 22
First Page : 5163
Last Page : 5167
Authors : Govek SP, Nagasawa JY, Douglas KL, Lai AG, Kahraman M, Bonnefous C, Aparicio AM, Darimont BD, Grillot KL, Joseph JD, Kaufman JA, Lee KJ, Lu N, Moon MJ, Prudente RY, Sensintaffar J, Rix PJ, Hager JH, Smith ND.
Abstract : Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
|
Displacement of [3H]-estradiol from recombinant human N-terminal His-tagged ERalpha LBD harboring C381S/C417S/C530S mutant expressed in Rosetta 2 DE3 competent cells after 1 hr by SPA binding assay
|
Homo sapiens
|
8.4
nM
|
|
Journal : J Med Chem
Title : Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
Year : 2017
Volume : 60
Issue : 7
First Page : 2790
Last Page : 2818
Authors : Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S.
Abstract : Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
|
Antagonist activity at ERalpha in human MCF7 cells assessed as inhibition of estrogen-induced transcription preincubated overnight followed by estrogen addition measured after 24 hrs by dual luciferase reporter gene assay
|
Homo sapiens
|
3.4
nM
|
|
Journal : J Med Chem
Title : Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
Year : 2017
Volume : 60
Issue : 7
First Page : 2790
Last Page : 2818
Authors : Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S.
Abstract : Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
|
Induction of ERalpha degradation in human MCF7 cells after 18 to 24 hrs by Western blot analysis
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Med Chem
Title : Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
Year : 2017
Volume : 60
Issue : 7
First Page : 2790
Last Page : 2818
Authors : Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S.
Abstract : Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
|
Induction of ERalpha degradation in human MCF7 cells assessed as inhibition of insulin-mediated cell proliferation after 6 days by Hoechst 33258 dye-based assay
|
Homo sapiens
|
0.06
nM
|
|
Journal : J Med Chem
Title : Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
Year : 2017
Volume : 60
Issue : 7
First Page : 2790
Last Page : 2818
Authors : Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S.
Abstract : Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
|
In vivo induction of ERalpha degradation in human MCF7 cells xenografted in immunocompromised nude mouse assessed as inhibition of ERalpha protein levels at at 250 mg/kg, sc administered once per week for 108 days measured at 24 hrs post last dose by ELISA relative to control
|
Homo sapiens
|
62.0
%
|
|
Journal : J Med Chem
Title : Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
Year : 2017
Volume : 60
Issue : 7
First Page : 2790
Last Page : 2818
Authors : Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S.
Abstract : Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
|
Induction of ERalpha degradation in human MCF7 cells after 18 hrs by Western blot analysis
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
Year : 2017
Volume : 60
Issue : 7
First Page : 2790
Last Page : 2818
Authors : Burks HE, Abrams T, Kirby CA, Baird J, Fekete A, Hamann LG, Kim S, Lombardo F, Loo A, Lubicka D, Macchi K, McDonnell DP, Mishina Y, Norris JD, Nunez J, Saran C, Sun Y, Thomsen NM, Wang C, Wang J, Peukert S.
Abstract : Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
|
Downregulation of human ERalpha in human MCF-7 cells after 24 hrs by in-cell Western immunoassay method
|
Homo sapiens
|
0.3
nM
|
|
Journal : J Med Chem
Title : Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells.
Year : 2017
Volume : 60
Issue : 14
First Page : 6321
Last Page : 6336
Authors : Min J, Guillen VS, Sharma A, Zhao Y, Ziegler Y, Gong P, Mayne CG, Srinivasan S, Kim SH, Carlson KE, Nettles KW, Katzenellenbogen BS, Katzenellenbogen JA.
Abstract : To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and amide analogs. All compounds were high affinity estrogen receptor α (ERα) ligands but displayed a range of efficacies and potencies as antiproliferative and ERα-downregulating agents. There were large differences in activity between compounds having minor structural changes, but antiproliferative and ERα-downregulating efficacies generally paralleled one another. Some compounds with side chain polar groups had particularly high affinities. The secondary carboxamides had the best cellular activities, and the 3-hydroxypropylamide was as efficacious as fulvestrant in suppressing cell proliferation and gene expression. This study has produced structurally novel antiestrogens based on a simple adamantyl core structure with acrylate side chains optimized for cellular antagonist activity.
|
Induction of selective estrogen receptor alpha degradation in human MCF7 cells harboring TK-ERE-Luc assessed as reduction in estradiol-induced transcriptional activity after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
3.4
nM
|
|
Journal : J Med Chem
Title : Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
Year : 2018
Volume : 61
Issue : 7
First Page : 2837
Last Page : 2864
Authors : Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S.
Abstract : In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
|
Induction of selective estrogen receptor alpha degradation in human MCF7 cells after 18 to 24 hrs by in-cell Western analysis
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
Year : 2018
Volume : 61
Issue : 7
First Page : 2837
Last Page : 2864
Authors : Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S.
Abstract : In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
|
Antiproliferative activity against human MCF7 cells after 6 days in presence of estradiol by CellTiter-Glo assay
|
Homo sapiens
|
4.4
nM
|
|
Journal : J Med Chem
Title : Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
Year : 2018
Volume : 61
Issue : 7
First Page : 2837
Last Page : 2864
Authors : Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S.
Abstract : In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
|
Induction of selective estrogen receptor alpha degradation in human MCF7 cells harboring TK-ERE-Luc assessed as reduction in estradiol-induced GREB1 mRNA expression after 24 hrs by TaqMan assay
|
Homo sapiens
|
3.8
nM
|
|
Journal : J Med Chem
Title : Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
Year : 2018
Volume : 61
Issue : 7
First Page : 2837
Last Page : 2864
Authors : Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S.
Abstract : In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
|
In vivo inhibition of ER protein level in NOD SCID gamma mouse xenografted with human MCF7 cells at 5 mg, sc administered once in a week for 48 days post tumor implantation measured 7 hrs post last dose by Western blot method relative to control
|
Mus musculus
|
67.0
%
|
|
Journal : J Med Chem
Title : Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
Year : 2018
Volume : 61
Issue : 7
First Page : 2837
Last Page : 2864
Authors : Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S.
Abstract : In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
|
Reduction in uterine wet weight in ethynyl estradiol-stimulated CD-IGS rat at 200 mg/kg, po dosed daily for 3 days by gavage followed 15 mins later by 0.1 mg/kg, po ethynyl estradiol and measured 24 hrs after last dose by immature rat uterine wet weight assay
|
Rattus norvegicus
|
110.0
%
|
|
Journal : J Med Chem
Title : Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer.
Year : 2018
Volume : 61
Issue : 17
First Page : 7917
Last Page : 7928
Authors : Nagasawa J, Govek S, Kahraman M, Lai A, Bonnefous C, Douglas K, Sensintaffar J, Lu N, Lee K, Aparicio A, Kaufman J, Qian J, Shao G, Prudente R, Joseph JD, Darimont B, Brigham D, Maheu K, Heyman R, Rix PJ, Hager JH, Smith ND.
Abstract : About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
|
Antiproliferative activity against human MCF7 cells after 6 days by WST-1 assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : ACS Med Chem Lett
Title : New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons.
Year : 2018
Volume : 9
Issue : 8
First Page : 803
Last Page : 808
Authors : Wang L, Guillen VS, Sharma N, Flessa K, Min J, Carlson KE, Toy W, Braqi S, Katzenellenbogen BS, Katzenellenbogen JA, Chandarlapaty S, Sharma A.
Abstract : An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.
|
Proteolysis targeting chimera activity in human MCF7 cells assessed as induction of E3 ubiquitin ligase-mediated ERalpha degradation by proteasome after 24 hrs by in-cell Western assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : ACS Med Chem Lett
Title : New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons.
Year : 2018
Volume : 9
Issue : 8
First Page : 803
Last Page : 808
Authors : Wang L, Guillen VS, Sharma N, Flessa K, Min J, Carlson KE, Toy W, Braqi S, Katzenellenbogen BS, Katzenellenbogen JA, Chandarlapaty S, Sharma A.
Abstract : An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.
|
Induction of ERalpha degradation in human MCF7 cells in phenol red free RPMI medium containing 5% charcoal-stripped FBS incubated for 4 hrs by IRDye 800CW/DRAQ5 dye based in-cell Western assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft.
Year : 2019
Volume : 29
Issue : 3
First Page : 367
Last Page : 372
Authors : Govek SP, Bonnefous C, Julien JD, Nagasawa JY, Kahraman M, Lai AG, Douglas KL, Aparicio AM, Darimont BD, Grillot KL, Joseph JD, Kaufman JA, Lee KJ, Lu N, Moon MJ, Prudente RY, Sensintaffar J, Rix PJ, Hager JH, Smith ND.
Abstract : Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
|
Antiproliferative activity against human MCF7 cells assessed as reduction in cell proliferation measured after 5 days by Cell-titer-Glo assay
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft.
Year : 2019
Volume : 29
Issue : 3
First Page : 367
Last Page : 372
Authors : Govek SP, Bonnefous C, Julien JD, Nagasawa JY, Kahraman M, Lai AG, Douglas KL, Aparicio AM, Darimont BD, Grillot KL, Joseph JD, Kaufman JA, Lee KJ, Lu N, Moon MJ, Prudente RY, Sensintaffar J, Rix PJ, Hager JH, Smith ND.
Abstract : Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
|
Antiproliferative activity against human MCF7:5C cells assessed as reduction in cell viability incubated for 7 days by Hoechst 33258 dye based assay
|
Homo sapiens
|
1.738
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer.
Year : 2019
Volume : 62
Issue : 24
First Page : 11301
Last Page : 11323
Authors : Lu Y, Gutgesell LM, Xiong R, Zhao J, Li Y, Rosales CI, Hollas M, Shen Z, Gordon-Blake J, Dye K, Wang Y, Lee S, Chen H, He D, Dubrovyskyii O, Zhao H, Huang F, Lasek AW, Tonetti DA, Thatcher GRJ.
Abstract : The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing <i>ESR1</i> mutations. A novel 3-oxyazetidine side chain was designed, leading to <b>37d</b>, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
|
Antiproliferative activity against human MCF7:WS8 cells assessed as reduction in cell viability incubated for 5 days by Hoechst 33258 dye based assay
|
Homo sapiens
|
0.6026
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer.
Year : 2019
Volume : 62
Issue : 24
First Page : 11301
Last Page : 11323
Authors : Lu Y, Gutgesell LM, Xiong R, Zhao J, Li Y, Rosales CI, Hollas M, Shen Z, Gordon-Blake J, Dye K, Wang Y, Lee S, Chen H, He D, Dubrovyskyii O, Zhao H, Huang F, Lasek AW, Tonetti DA, Thatcher GRJ.
Abstract : The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing <i>ESR1</i> mutations. A novel 3-oxyazetidine side chain was designed, leading to <b>37d</b>, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
|
Inhibition of ERalpha in human MCF7:WS8 cells assessed as increase in degradation of ERalpha incubated for 24 hrs by In-Cell Western assay
|
Homo sapiens
|
1.585
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer.
Year : 2019
Volume : 62
Issue : 24
First Page : 11301
Last Page : 11323
Authors : Lu Y, Gutgesell LM, Xiong R, Zhao J, Li Y, Rosales CI, Hollas M, Shen Z, Gordon-Blake J, Dye K, Wang Y, Lee S, Chen H, He D, Dubrovyskyii O, Zhao H, Huang F, Lasek AW, Tonetti DA, Thatcher GRJ.
Abstract : The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing <i>ESR1</i> mutations. A novel 3-oxyazetidine side chain was designed, leading to <b>37d</b>, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
|
Antagonist activity at ERalpha in human MCF7 cells assessed as inhibition of estradiol-driven cell growth measured after 7 days by SYTOX green-based assay
|
Homo sapiens
|
5.012
nM
|
|
Journal : J Med Chem
Title : Tricyclic Indazoles-A Novel Class of Selective Estrogen Receptor Degrader Antagonists.
Year : 2019
Volume : 62
Issue : 3
First Page : 1593
Last Page : 1608
Authors : Scott JS, Bailey A, Buttar D, Carbajo RJ, Curwen J, Davey PRJ, Davies RDM, Degorce SL, Donald C, Gangl E, Greenwood R, Groombridge SD, Johnson T, Lamont S, Lawson M, Lister A, Morrow CJ, Moss TA, Pink JH, Polanski R.
Abstract : Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
|
Antagonist activity at FLAG-tagged ERalpha (unknown origin) expressed in HEK293 cells assessed as reduction in E2-induced ER-alpha-mediated transcriptional activity by luciferase reporter gene assay
|
Homo sapiens
|
0.78
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton.
Year : 2019
Volume : 27
Issue : 10
First Page : 1952
Last Page : 1961
Authors : Nanjyo S, Ohgane K, Yoshioka H, Makishima M, Hashimoto Y, Noguchi-Yachide T.
Abstract : Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.
|
Selective estrogen receptor down-regulator activity at FLAG-tagged ERalpha (unknown origin) expressed in HEK293 cells assessed as induction of ERalpha degradation by luciferase reporter gene assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton.
Year : 2019
Volume : 27
Issue : 10
First Page : 1952
Last Page : 1961
Authors : Nanjyo S, Ohgane K, Yoshioka H, Makishima M, Hashimoto Y, Noguchi-Yachide T.
Abstract : Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.
|
Selective estrogen receptor down-regulator activity at FLAG-tagged ERalpha (unknown origin) expressed in HEK293 cells assessed as induction of ERalpha degradation by measuring dissociation constant for degradation by luciferase reporter gene assay relative to untreated control
|
Homo sapiens
|
4.69
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton.
Year : 2019
Volume : 27
Issue : 10
First Page : 1952
Last Page : 1961
Authors : Nanjyo S, Ohgane K, Yoshioka H, Makishima M, Hashimoto Y, Noguchi-Yachide T.
Abstract : Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.
|
Antiproliferative activity against human MCF7 cells after 5 days by coulter counter analysis
|
Homo sapiens
|
1.5
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Antiproliferative activity against human T47D cells after 5 days by coulter counter analysis
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Antiproliferative activity against human tamoxifen-resistant MCF7 cells after 5 days by coulter counter analysis
|
Homo sapiens
|
44.0
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Antiproliferative activity against human tamoxifen-resistant T47D cells over-expressing PKC-alpha after 5 days by coulter counter analysis
|
Homo sapiens
|
42.0
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Displacement of fluoromone ligand from recombinant ER-alpha (unknown origin) by LanthaScreen TR-FRET assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Downregulation of ER-alpha expression in human T47D cells measured after 5 days by Western blot analysis
|
Homo sapiens
|
9.3
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Downregulation of ER-alpha expression in human tamoxifen-resistant T47D cells over-expressing PKC-alpha measured after 5 days by Western blot analysis
|
Homo sapiens
|
8.5
nM
|
|
Journal : J Med Chem
Title : Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD).
Year : 2016
Volume : 59
Issue : 17
First Page : 8134
Last Page : 8140
Authors : Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G.
Abstract : Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD.
|
Induction of ERalpha degradation in human MCF7 cells after 4 hrs by FITC/Hoechst staining based immunofluorescence imaging analysis
|
Homo sapiens
|
0.32
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Year : 2020
Volume : 11
Issue : 6
First Page : 1342
Last Page : 1347
Authors : Liang J, Blake R, Chang J, Friedman LS, Goodacre S, Hartman S, Ingalla ER, Kiefer JR, Kleinheinz T, Labadie S, Li J, Lai KW, Liao J, Mody V, McLean N, Metcalfe C, Nannini M, Otwine D, Ran Y, Ray N, Roussel F, Sambrone A, Sampath D, Vinogradova M, Wai J, Wang T, Yeap K, Young A, Zbieg J, Zhang B, Zheng X, Zhong Y, Wang X.
Abstract : Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule <b>12</b> (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of <b>6</b> that showed ionic interaction of azetidine with Asp351 residue. Importantly, <b>12</b> showed favorable metabolic stability and good oral exposure. <b>12</b> exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
|
Antiproliferative activity against human MCF7 cells assessed as reduction in cell viability after 72 hrs by Celltiter-Glo assay
|
Homo sapiens
|
2.6
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Year : 2020
Volume : 11
Issue : 6
First Page : 1342
Last Page : 1347
Authors : Liang J, Blake R, Chang J, Friedman LS, Goodacre S, Hartman S, Ingalla ER, Kiefer JR, Kleinheinz T, Labadie S, Li J, Lai KW, Liao J, Mody V, McLean N, Metcalfe C, Nannini M, Otwine D, Ran Y, Ray N, Roussel F, Sambrone A, Sampath D, Vinogradova M, Wai J, Wang T, Yeap K, Young A, Zbieg J, Zhang B, Zheng X, Zhong Y, Wang X.
Abstract : Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule <b>12</b> (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of <b>6</b> that showed ionic interaction of azetidine with Asp351 residue. Importantly, <b>12</b> showed favorable metabolic stability and good oral exposure. <b>12</b> exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
|
Antiproliferative activity against human T47D cells assessed as reduction in cell viability
|
Homo sapiens
|
3.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Year : 2020
Volume : 11
Issue : 6
First Page : 1342
Last Page : 1347
Authors : Liang J, Blake R, Chang J, Friedman LS, Goodacre S, Hartman S, Ingalla ER, Kiefer JR, Kleinheinz T, Labadie S, Li J, Lai KW, Liao J, Mody V, McLean N, Metcalfe C, Nannini M, Otwine D, Ran Y, Ray N, Roussel F, Sambrone A, Sampath D, Vinogradova M, Wai J, Wang T, Yeap K, Young A, Zbieg J, Zhang B, Zheng X, Zhong Y, Wang X.
Abstract : Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule <b>12</b> (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of <b>6</b> that showed ionic interaction of azetidine with Asp351 residue. Importantly, <b>12</b> showed favorable metabolic stability and good oral exposure. <b>12</b> exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
|
Induction of ERalpha degradation in human T47D cells
|
Homo sapiens
|
0.84
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Year : 2020
Volume : 11
Issue : 6
First Page : 1342
Last Page : 1347
Authors : Liang J, Blake R, Chang J, Friedman LS, Goodacre S, Hartman S, Ingalla ER, Kiefer JR, Kleinheinz T, Labadie S, Li J, Lai KW, Liao J, Mody V, McLean N, Metcalfe C, Nannini M, Otwine D, Ran Y, Ray N, Roussel F, Sambrone A, Sampath D, Vinogradova M, Wai J, Wang T, Yeap K, Young A, Zbieg J, Zhang B, Zheng X, Zhong Y, Wang X.
Abstract : Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule <b>12</b> (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of <b>6</b> that showed ionic interaction of azetidine with Asp351 residue. Importantly, <b>12</b> showed favorable metabolic stability and good oral exposure. <b>12</b> exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
|
Displacement of fluorescent-labelled E2 from recombinant human GST-tagged ERalpha by LanthaScreen TR-FRET assay
|
Homo sapiens
|
2.85
nM
|
|
Journal : Eur J Med Chem
Title : Development of bivalent triarylalkene- and cyclofenil-derived dual estrogen receptor antagonists and downregulators.
Year : 2020
Volume : 192
First Page : 112191
Last Page : 112191
Authors : Knox A,Kalchschmid C,Schuster D,Gaggia F,Manzl C,Baecker D,Gust R
Abstract : Up to 80% of mammary carcinoma initially exhibit estrogen-dependent growth, which can be treated by aromatase inhibitors or SERMs/SERDs. To increase the options after failure of the hormonal therapy with these drugs, the search for alternatives with a different mode of action to prevent estrogen action is of high relevance. Therefore, this study focused on the inhibition of coactivator recruitment at the estrogen receptor (ER) by targeted attachment of bivalent compounds at the coactivator binding site besides the primary binding at the ligand binding domain. Eight homodimeric 4-[1-(4-hydroxyphenyl)-2-phenyl-1-butenyl]cinnamic acid (GW7604)- or cyclofenilacrylic acid-based ER ligands with diaminoalkane linkers (C2-C5) were synthesized and their effects on the ER subtypes were assessed in vitro. All compounds possessed full antagonistic potency at ERα/β as determined in a transactivation assay. Furthermore, they exerted medium downregulatory effects dependent on the spacer length and did not stimulate the ER expression as observed for 4-hydroxytamoxifen. The cyclofenil-derived dimer with C4 spacer (15b) showed the highest binding affinity to ERα (RBA = 79.2%) and downregulated the ER content in MCF-7 cells with an efficiency of 38% at 1 μM.
|
Displacement of fluorescent-labelled E2 from recombinant human GST-tagged ERbeta by LanthaScreen TR-FRET assay
|
Homo sapiens
|
10.2
nM
|
|
Journal : Eur J Med Chem
Title : Development of bivalent triarylalkene- and cyclofenil-derived dual estrogen receptor antagonists and downregulators.
Year : 2020
Volume : 192
First Page : 112191
Last Page : 112191
Authors : Knox A,Kalchschmid C,Schuster D,Gaggia F,Manzl C,Baecker D,Gust R
Abstract : Up to 80% of mammary carcinoma initially exhibit estrogen-dependent growth, which can be treated by aromatase inhibitors or SERMs/SERDs. To increase the options after failure of the hormonal therapy with these drugs, the search for alternatives with a different mode of action to prevent estrogen action is of high relevance. Therefore, this study focused on the inhibition of coactivator recruitment at the estrogen receptor (ER) by targeted attachment of bivalent compounds at the coactivator binding site besides the primary binding at the ligand binding domain. Eight homodimeric 4-[1-(4-hydroxyphenyl)-2-phenyl-1-butenyl]cinnamic acid (GW7604)- or cyclofenilacrylic acid-based ER ligands with diaminoalkane linkers (C2-C5) were synthesized and their effects on the ER subtypes were assessed in vitro. All compounds possessed full antagonistic potency at ERα/β as determined in a transactivation assay. Furthermore, they exerted medium downregulatory effects dependent on the spacer length and did not stimulate the ER expression as observed for 4-hydroxytamoxifen. The cyclofenil-derived dimer with C4 spacer (15b) showed the highest binding affinity to ERα (RBA = 79.2%) and downregulated the ER content in MCF-7 cells with an efficiency of 38% at 1 μM.
|
Antagonist activity at estrogen receptor in human T47D cells incubated for 18 hrs by ultra high sensitivity luminescence reporter gene assay
|
Homo sapiens
|
0.25
nM
|
|
|
Antiproliferative activity against human MCF-7 cells incubated for 72 hrs by Cell-titer Glo assay
|
Homo sapiens
|
2.4
nM
|
|
|
Displacement of fluorescent estradiol from full-length ERalpha (unknown origin) measured after 2 hrs by fluorescence polarization assay
|
Homo sapiens
|
88.5
nM
|
|
|
Displacement of fluorescent-labeled E2 from LBD of ERalpha (unknown origin) by TR-FRET assay
|
Homo sapiens
|
2.85
nM
|
|
|
Displacement of fluorescent-labeled E2 from LBD of ERbeta (unknown origin) by TR-FRET assay
|
Homo sapiens
|
10.2
nM
|
|
|
Antiproliferative activity against human ER-positive MCF7 cells assessed as reduction in cell viability measured after 120 hrs by crystal violet staining based assay
|
Homo sapiens
|
0.58
nM
|
|
|
Antiproliferative activity against human MCF-7/TAMR-1 cells assessed as reduction in cell viability measured after 120 hrs by crystal violet staining based assayy
|
Homo sapiens
|
1.8
nM
|
|
