|
Binding affinity for human heat shock protein 90 in scintillation proximity assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of 7-carbamate analogs of geldanamycin.
Year : 2005
Volume : 15
Issue : 22
First Page : 5016
Last Page : 5021
Authors : Rastelli G, Tian ZQ, Wang Z, Myles D, Liu Y.
Abstract : The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl)amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive.
|
Cytotoxicity against SKBr3 cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of 7-carbamate analogs of geldanamycin.
Year : 2005
Volume : 15
Issue : 22
First Page : 5016
Last Page : 5021
Authors : Rastelli G, Tian ZQ, Wang Z, Myles D, Liu Y.
Abstract : The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl)amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive.
|
Inhibition of BODIPY-AG binding to human HSP90
|
Homo sapiens
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
Year : 2006
Volume : 49
Issue : 15
First Page : 4606
Last Page : 4615
Authors : Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
|
Inhibition of BODIPY-AG binding to dog Grp94
|
Canis lupus familiaris
|
65.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
Year : 2006
Volume : 49
Issue : 15
First Page : 4606
Last Page : 4615
Authors : Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
|
Degradation of Her2 in SKBR3 cells
|
Homo sapiens
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
Year : 2006
Volume : 49
Issue : 15
First Page : 4606
Last Page : 4615
Authors : Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
|
Degradation of Her2 in SKOV3 cells
|
Homo sapiens
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
Year : 2006
Volume : 49
Issue : 15
First Page : 4606
Last Page : 4615
Authors : Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
|
Upregulation of Hsp70 in SKBR3 cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
Year : 2006
Volume : 49
Issue : 15
First Page : 4606
Last Page : 4615
Authors : Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
|
Upregulation of Hsp70 in SKOV3 cells
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
Year : 2006
Volume : 49
Issue : 15
First Page : 4606
Last Page : 4615
Authors : Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
|
Inhibition of HIF1 activation in human AGS cells assessed as inhibition of hypoxia-induced luciferase expression after 16 hrs by reporter assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : J. Nat. Prod.
Title : Abietane diterpenes from Salvia miltiorrhiza inhibit the activation of hypoxia-inducible factor-1.
Year : 2007
Volume : 70
Issue : 7
First Page : 1093
Last Page : 1097
Authors : Dat NT, Jin X, Lee JH, Lee D, Hong YS, Lee K, Kim YH, Lee JJ.
Abstract : The hypoxia-inducible factor-1 (HIF-1) has been known to be correlated to the adaptation and proliferation of tumor cells; therefore HIF-1 has become an important target in the development of anticancer drugs. A phytochemical study of the CHCl3-soluble fraction of Salvia miltiorrhiza, which strongly inhibited hypoxia-induced reporter gene expression, led to the isolation of 12 abietane-type diterpenes. Of these compounds, sibiriquinone A (1), sibiriquinone B (2), cryptotanshinone (3), and dihydrotanshinone I (4) potently inhibited hypoxia-induced luciferase expression with IC50 values of 0.34, 3.36, 1.58, and 2.05 microM on AGS cells, a human gastric cancer cell line, and 0.28, 3.18, 1.36, and 2.29 microM on Hep3B cells, a human hepatocarcinoma cell line, respectively. Consistently, 1 and 4 dose-dependently suppressed the HIF-1alpha accumulation and 1 inhibited mRNA expression of vascular endothelial growth factor (VEGF) under hypoxia. These results suggest that the anticancer activity of tanshinones is likely at least in part associated with their inhibition of HIF-1 accumulation.
|
Inhibition of HIF1 activation in human Hep3B cells assessed as inhibition of hypoxia-induced luciferase expression after 16 hrs by reporter assay
|
Homo sapiens
|
61.0
nM
|
|
Journal : J. Nat. Prod.
Title : Abietane diterpenes from Salvia miltiorrhiza inhibit the activation of hypoxia-inducible factor-1.
Year : 2007
Volume : 70
Issue : 7
First Page : 1093
Last Page : 1097
Authors : Dat NT, Jin X, Lee JH, Lee D, Hong YS, Lee K, Kim YH, Lee JJ.
Abstract : The hypoxia-inducible factor-1 (HIF-1) has been known to be correlated to the adaptation and proliferation of tumor cells; therefore HIF-1 has become an important target in the development of anticancer drugs. A phytochemical study of the CHCl3-soluble fraction of Salvia miltiorrhiza, which strongly inhibited hypoxia-induced reporter gene expression, led to the isolation of 12 abietane-type diterpenes. Of these compounds, sibiriquinone A (1), sibiriquinone B (2), cryptotanshinone (3), and dihydrotanshinone I (4) potently inhibited hypoxia-induced luciferase expression with IC50 values of 0.34, 3.36, 1.58, and 2.05 microM on AGS cells, a human gastric cancer cell line, and 0.28, 3.18, 1.36, and 2.29 microM on Hep3B cells, a human hepatocarcinoma cell line, respectively. Consistently, 1 and 4 dose-dependently suppressed the HIF-1alpha accumulation and 1 inhibited mRNA expression of vascular endothelial growth factor (VEGF) under hypoxia. These results suggest that the anticancer activity of tanshinones is likely at least in part associated with their inhibition of HIF-1 accumulation.
|
Inhibition of hypoxia-induced HIF1 activation in human AGS cells by reporter gene assay
|
Homo sapiens
|
3.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hypoxia-inducible factor-1 and nuclear factor-kappaB inhibitory meroterpene analogues of bakuchiol, a constituent of the seeds of Psoralea corylifolia.
Year : 2008
Volume : 18
Issue : 8
First Page : 2619
Last Page : 2623
Authors : Wu CZ, Hong SS, Cai XF, Dat NT, Nan JX, Hwang BY, Lee JJ, Lee D.
Abstract : Two new meroterpenoids, 12,13-dihydro-12,13-dihydroxybakuchiol (2) and (12'S)-bisbakuchiol C (3), were isolated from the seeds of Psoralea corylifolia L. (Fabaceae). The structures of 2 and 3 were elucidated by spectroscopic and chemical methods. Six meroterpenoids isolated from P. corylifolia and three semi-synthetic analogues were evaluated for HIF-1 and NF-kappaB inhibition, and O-methyl and O-ethylbakuchiols (6 and 7) inhibited HIF-1 and NF-kappaB activation without significantly decreasing the viability of the AGS and HeLa cells, respectively.
|
Inhibition of TNF-alpha-induced NF-kappaB activation in human HeLa cells
|
Homo sapiens
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hypoxia-inducible factor-1 and nuclear factor-kappaB inhibitory meroterpene analogues of bakuchiol, a constituent of the seeds of Psoralea corylifolia.
Year : 2008
Volume : 18
Issue : 8
First Page : 2619
Last Page : 2623
Authors : Wu CZ, Hong SS, Cai XF, Dat NT, Nan JX, Hwang BY, Lee JJ, Lee D.
Abstract : Two new meroterpenoids, 12,13-dihydro-12,13-dihydroxybakuchiol (2) and (12'S)-bisbakuchiol C (3), were isolated from the seeds of Psoralea corylifolia L. (Fabaceae). The structures of 2 and 3 were elucidated by spectroscopic and chemical methods. Six meroterpenoids isolated from P. corylifolia and three semi-synthetic analogues were evaluated for HIF-1 and NF-kappaB inhibition, and O-methyl and O-ethylbakuchiols (6 and 7) inhibited HIF-1 and NF-kappaB activation without significantly decreasing the viability of the AGS and HeLa cells, respectively.
|
Inhibition of Hsp90 in human MDA-MB-231 cells assessed as Akt degradation
|
Homo sapiens
|
17.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Year : 2008
Volume : 18
Issue : 23
First Page : 6273
Last Page : 6278
Authors : Kung PP, Funk L, Meng J, Collins M, Zhou JZ, Johnson MC, Ekker A, Wang J, Mehta P, Yin MJ, Rodgers C, Davies JF, Bayman E, Smeal T, Maegley KA, Gehring MR.
Abstract : Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
|
Inhibition of Hsp90 in human MDA-MB-231 cells assessed as her2 degradation
|
Homo sapiens
|
4.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Year : 2008
Volume : 18
Issue : 23
First Page : 6273
Last Page : 6278
Authors : Kung PP, Funk L, Meng J, Collins M, Zhou JZ, Johnson MC, Ekker A, Wang J, Mehta P, Yin MJ, Rodgers C, Davies JF, Bayman E, Smeal T, Maegley KA, Gehring MR.
Abstract : Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
|
Cytotoxicity against human MDA-MB-231 cells by MTT assay
|
Homo sapiens
|
5.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Year : 2008
Volume : 18
Issue : 23
First Page : 6273
Last Page : 6278
Authors : Kung PP, Funk L, Meng J, Collins M, Zhou JZ, Johnson MC, Ekker A, Wang J, Mehta P, Yin MJ, Rodgers C, Davies JF, Bayman E, Smeal T, Maegley KA, Gehring MR.
Abstract : Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
|
Inhibition of Hsp90 in human A2058 cells assessed as Akt degradation
|
Homo sapiens
|
24.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Year : 2008
Volume : 18
Issue : 23
First Page : 6273
Last Page : 6278
Authors : Kung PP, Funk L, Meng J, Collins M, Zhou JZ, Johnson MC, Ekker A, Wang J, Mehta P, Yin MJ, Rodgers C, Davies JF, Bayman E, Smeal T, Maegley KA, Gehring MR.
Abstract : Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
|
Cytotoxicity against human A2058 cells by MTT assay
|
Homo sapiens
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Year : 2008
Volume : 18
Issue : 23
First Page : 6273
Last Page : 6278
Authors : Kung PP, Funk L, Meng J, Collins M, Zhou JZ, Johnson MC, Ekker A, Wang J, Mehta P, Yin MJ, Rodgers C, Davies JF, Bayman E, Smeal T, Maegley KA, Gehring MR.
Abstract : Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
|
Inhibition of Hsp90 in human A2058 cells
|
Homo sapiens
|
7.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Year : 2008
Volume : 18
Issue : 23
First Page : 6273
Last Page : 6278
Authors : Kung PP, Funk L, Meng J, Collins M, Zhou JZ, Johnson MC, Ekker A, Wang J, Mehta P, Yin MJ, Rodgers C, Davies JF, Bayman E, Smeal T, Maegley KA, Gehring MR.
Abstract : Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
|
Cytotoxicity against human SKBR3 cells after 72 hrs by celltiter-glo assay
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cytotoxic C-11 modified geldanamycin analogues.
Year : 2009
Volume : 52
Issue : 10
First Page : 3265
Last Page : 3273
Authors : Tian ZQ, Wang Z, MacMillan KS, Zhou Y, Carreras CW, Mueller T, Myles DC, Liu Y.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
|
Binding affinity to human recombinant HSP90
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cytotoxic C-11 modified geldanamycin analogues.
Year : 2009
Volume : 52
Issue : 10
First Page : 3265
Last Page : 3273
Authors : Tian ZQ, Wang Z, MacMillan KS, Zhou Y, Carreras CW, Mueller T, Myles DC, Liu Y.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
|
Cytotoxicity against human MCF7 cells after 72 hrs by celltiter-glo assay
|
Homo sapiens
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cytotoxic C-11 modified geldanamycin analogues.
Year : 2009
Volume : 52
Issue : 10
First Page : 3265
Last Page : 3273
Authors : Tian ZQ, Wang Z, MacMillan KS, Zhou Y, Carreras CW, Mueller T, Myles DC, Liu Y.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
|
Cytotoxicity against human SKOV3 cells after 72 hrs by celltiter-glo assay
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cytotoxic C-11 modified geldanamycin analogues.
Year : 2009
Volume : 52
Issue : 10
First Page : 3265
Last Page : 3273
Authors : Tian ZQ, Wang Z, MacMillan KS, Zhou Y, Carreras CW, Mueller T, Myles DC, Liu Y.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
|
Cytotoxicity against human A549 cells after 72 hrs by celltiter-glo assay
|
Homo sapiens
|
68.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cytotoxic C-11 modified geldanamycin analogues.
Year : 2009
Volume : 52
Issue : 10
First Page : 3265
Last Page : 3273
Authors : Tian ZQ, Wang Z, MacMillan KS, Zhou Y, Carreras CW, Mueller T, Myles DC, Liu Y.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
|
Cytotoxicity against human CCRF-CEM cells after 72 hrs by celltiter-96 aqueous one solution assay
|
Homo sapiens
|
540.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cytotoxic C-11 modified geldanamycin analogues.
Year : 2009
Volume : 52
Issue : 10
First Page : 3265
Last Page : 3273
Authors : Tian ZQ, Wang Z, MacMillan KS, Zhou Y, Carreras CW, Mueller T, Myles DC, Liu Y.
Abstract : 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
|
Cytotoxicity against human MCF7 cells after 72 hrs in presence of NQO1 inhibitor dicoumarol
|
Homo sapiens
|
862.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Cytotoxicity against human SKBR3 cells after 72 hrs in presence of NQO1 inhibitor dicoumarol
|
Homo sapiens
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Binding affinity to human recombinant Hsp90alpha N-terminal domain by scintillation proximity assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Binding affinity to human recombinant Hsp90alpha N-terminal domain by isothermal titration calorimetry
|
Homo sapiens
|
87.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Cytotoxicity against human SKBR3 cells after 72 hrs
|
Homo sapiens
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Cytotoxicity against human SKOV3 cells after 72 hrs
|
Homo sapiens
|
122.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Cytotoxicity against human HCT116 cells after 72 hrs
|
Homo sapiens
|
57.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Cytotoxicity against human MCF7 cells after 72 hrs
|
Homo sapiens
|
71.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus.
Year : 2009
Volume : 52
Issue : 6
First Page : 1518
Last Page : 1521
Authors : Menzella HG, Tran TT, Carney JR, Lau-Wee J, Galazzo J, Reeves CD, Carreras C, Mukadam S, Eng S, Zhong Z, Timmermans PB, Murli S, Ashley GW.
Abstract : Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
|
Binding affinity to Hsp90 in human SKBR3 cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery and development of heat shock protein 90 inhibitors.
Year : 2009
Volume : 17
Issue : 6
First Page : 2225
Last Page : 2235
Authors : Taldone T, Sun W, Chiosis G.
Abstract : Heat shock protein 90 (Hsp90) is an important target in cancer because of its role in maintaining transformation and has recently become the focus of several drug discovery and development efforts. While compounds with different modes of action are known, the focus of this review is on those classes of compounds which inhibit Hsp90 by binding to the N-terminal ATP pocket. These include natural product inhibitors such as geldanamycin and radicicol and synthetic inhibitors comprised of purines, pyrazoles, isoxazoles and other scaffolds. The synthetic inhibitors have been discovered either by structure-based design, high throughput screening and more recently using fragment-based design and virtual screening techniques. This review will discuss the discovery of these different classes, as well as their development as potential clinical agents.
|
Inhibition of hypoxia-induced HIF1alpha protein accumulation in human Hep3B cells treated for 30 mins measured after 12 hrs by Western blot analysis
|
Homo sapiens
|
57.2
nM
|
|
Journal : J. Nat. Prod.
Title : Hypoxia-inducible factor-1 inhibitory benzofurans and chalcone-derived diels-alder adducts from Morus species.
Year : 2009
Volume : 72
Issue : 1
First Page : 39
Last Page : 43
Authors : Dat NT, Jin X, Lee K, Hong YS, Kim YH, Lee JJ.
Abstract : Hypoxia-inducible factor-1 (HIF-1) is the central mediator of cellular responses to low oxygen concentrations and vital to many aspects of cancer biology. Bioassay-guided fractionation of the chloroform-soluble extracts of Morus species using a hypoxia response element (HRE)-dependent reporter assay led to identification of six benzofurans (1-6) and two chalcone-derived Diels-Alder adducts (7, 8) from Mori Cortex Radicis and three prenylated benzofurans (9-11) and four chalcone-derived Diels-Alder adducts (12-15) from Morus bombycis. The structure of the new 2-arylbenzofuran-type compound, moracin Q (3), was elucidated by spectroscopic methods, and the absolute configuration of 2 was determined for the first time. The selected compounds (1-3, 5, 7, 9, 10, and 12) from the cell-based reporter assay were found to inhibit hypoxia-induced HIF-1alpha accumulation in a dose-dependent manner in human hepatocelluar carcinoma cell-line Hep3B cells. Furthermore, these compounds were also active against hypoxia-induced vascular endothelial growth factor (VEGF) secretion in Hep3B cells.
|
Inhibition of hypoxia-induced VEGF protein secretion in human Hep3B cells after 16 hrs by ELISA
|
Homo sapiens
|
79.5
nM
|
|
Journal : J. Nat. Prod.
Title : Hypoxia-inducible factor-1 inhibitory benzofurans and chalcone-derived diels-alder adducts from Morus species.
Year : 2009
Volume : 72
Issue : 1
First Page : 39
Last Page : 43
Authors : Dat NT, Jin X, Lee K, Hong YS, Kim YH, Lee JJ.
Abstract : Hypoxia-inducible factor-1 (HIF-1) is the central mediator of cellular responses to low oxygen concentrations and vital to many aspects of cancer biology. Bioassay-guided fractionation of the chloroform-soluble extracts of Morus species using a hypoxia response element (HRE)-dependent reporter assay led to identification of six benzofurans (1-6) and two chalcone-derived Diels-Alder adducts (7, 8) from Mori Cortex Radicis and three prenylated benzofurans (9-11) and four chalcone-derived Diels-Alder adducts (12-15) from Morus bombycis. The structure of the new 2-arylbenzofuran-type compound, moracin Q (3), was elucidated by spectroscopic methods, and the absolute configuration of 2 was determined for the first time. The selected compounds (1-3, 5, 7, 9, 10, and 12) from the cell-based reporter assay were found to inhibit hypoxia-induced HIF-1alpha accumulation in a dose-dependent manner in human hepatocelluar carcinoma cell-line Hep3B cells. Furthermore, these compounds were also active against hypoxia-induced vascular endothelial growth factor (VEGF) secretion in Hep3B cells.
|
Displacement of [3H]pGA from His-tagged Hsp90 by scintillation proximity assay
|
None
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.
Year : 2010
Volume : 53
Issue : 1
First Page : 499
Last Page : 503
Authors : Kung PP, Huang B, Zhang G, Zhou JZ, Wang J, Digits JA, Skaptason J, Yamazaki S, Neul D, Zientek M, Elleraas J, Mehta P, Yin MJ, Hickey MJ, Gajiwala KS, Rodgers C, Davies JF, Gehring MR.
Abstract : The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
|
Inhibition of Hsp90 in human H1299 assessed as degradation of Hsp90 client protein Akt
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.
Year : 2010
Volume : 53
Issue : 1
First Page : 499
Last Page : 503
Authors : Kung PP, Huang B, Zhang G, Zhou JZ, Wang J, Digits JA, Skaptason J, Yamazaki S, Neul D, Zientek M, Elleraas J, Mehta P, Yin MJ, Hickey MJ, Gajiwala KS, Rodgers C, Davies JF, Gehring MR.
Abstract : The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
|
Inhibition of hypoxia-induced HIF1alpha protein accumulation in human Hep3B cells treated for 30 mins measured after 12 hrs by Western blot analysis
|
Homo sapiens
|
57.0
nM
|
|
Journal : J. Nat. Prod.
Title : An isoaurone and other constituents from Trichosanthes kirilowii seeds inhibit hypoxia-inducible factor-1 and nuclear factor-kappaB.
Year : 2010
Volume : 73
Issue : 6
First Page : 1167
Last Page : 1169
Authors : Dat NT, Jin X, Hong YS, Lee JJ.
Abstract : Hypoxia-inducible factor-1 and nuclear factor-kappaB have become important targets in cancer treatment due to their critical role in the regulation of genes involved in tumorigenesis. Bioassay-guided fractionation of the methanol extract of Trichosanthes kirilowii seeds led to the isolation of a naturally rare isoaurone, 4',6-dihydroxy-4-methoxyisoaurone (1), together with three known compounds, cucurbitacin B (2), 6-(3-hydroxy-4-methoxystyryl)-4-methoxy-2H-pyran-2-one (3), and blumenol A (4). All compounds inhibited HIF-1 and NF-kappaB activities in reporter assays. Compounds 1-3 potently inhibited HIF-1alpha accumulation and VEGF secretion under hypoxic condition. These results suggest that the tumor cell growth inhibitory activity of T. kirilowii is likely associated with the inhibition of HIF-1 and NF-kappaB activities.
|
Inhibition of hypoxia-induced VEGF protein secretion in human Hep3B cells after 16 hrs by ELISA
|
Homo sapiens
|
79.0
nM
|
|
Journal : J. Nat. Prod.
Title : An isoaurone and other constituents from Trichosanthes kirilowii seeds inhibit hypoxia-inducible factor-1 and nuclear factor-kappaB.
Year : 2010
Volume : 73
Issue : 6
First Page : 1167
Last Page : 1169
Authors : Dat NT, Jin X, Hong YS, Lee JJ.
Abstract : Hypoxia-inducible factor-1 and nuclear factor-kappaB have become important targets in cancer treatment due to their critical role in the regulation of genes involved in tumorigenesis. Bioassay-guided fractionation of the methanol extract of Trichosanthes kirilowii seeds led to the isolation of a naturally rare isoaurone, 4',6-dihydroxy-4-methoxyisoaurone (1), together with three known compounds, cucurbitacin B (2), 6-(3-hydroxy-4-methoxystyryl)-4-methoxy-2H-pyran-2-one (3), and blumenol A (4). All compounds inhibited HIF-1 and NF-kappaB activities in reporter assays. Compounds 1-3 potently inhibited HIF-1alpha accumulation and VEGF secretion under hypoxic condition. These results suggest that the tumor cell growth inhibitory activity of T. kirilowii is likely associated with the inhibition of HIF-1 and NF-kappaB activities.
|
Binding affinity to Hsp90 N-terminal ATPase domain by isothermal titration calorimetry assay
|
None
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Cytotoxicity against human HCT116 cells by Alamar blue assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 infected in human HuH7 cells assessed as GAPDH RNA or 18S rRNA level after 3 days selected with 40 nM HCV-796 and 800 nM boceprevir by qRT-PCR analysis
|
Hepatitis C virus
|
3.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 infected in human HuH7 cells assessed as GAPDH RNA or 18S rRNA level after 3 days by qRT-PCR analysis
|
Hepatitis C virus
|
1.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Inhibition of human HSP90 in human NCI-H1299 cells assessed as Akt degradation after 24 hrs by luminex assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.
Year : 2011
Volume : 54
Issue : 9
First Page : 3368
Last Page : 3385
Authors : Zehnder L, Bennett M, Meng J, Huang B, Ninkovic S, Wang F, Braganza J, Tatlock J, Jewell T, Zhou JZ, Burke B, Wang J, Maegley K, Mehta PP, Yin MJ, Gajiwala KS, Hickey MJ, Yamazaki S, Smith E, Kang P, Sistla A, Dovalsantos E, Gehring MR, Kania R, Wythes M, Kung PP.
Abstract : A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.
|
Displacement of [3H]-(R)-2-(5-chloro-2,4-dihydroxybenzoyl)-N-ethylisoindoline-1-carboxamide from human his(6)-tagged HSP90alpha after 30 mins by scintillation proximity assay
|
Homo sapiens
|
680.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.
Year : 2011
Volume : 54
Issue : 9
First Page : 3368
Last Page : 3385
Authors : Zehnder L, Bennett M, Meng J, Huang B, Ninkovic S, Wang F, Braganza J, Tatlock J, Jewell T, Zhou JZ, Burke B, Wang J, Maegley K, Mehta PP, Yin MJ, Gajiwala KS, Hickey MJ, Yamazaki S, Smith E, Kang P, Sistla A, Dovalsantos E, Gehring MR, Kania R, Wythes M, Kung PP.
Abstract : A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.
|
Inhibition of Hsp90 in human COLO205 cells xenografted in mouse assessed as Raf1 degradation at 100 mg/kg administered QD for 2 days measured 8 hrs post-last dose
|
Mus musculus
|
84.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90.
Year : 2012
Volume : 22
Issue : 17
First Page : 5396
Last Page : 5404
Authors : Bussenius J, Blazey CM, Aay N, Anand NK, Arcalas A, Baik T, Bowles OJ, Buhr CA, Costanzo S, Curtis JK, DeFina SC, Dubenko L, Heuer TS, Huang P, Jaeger C, Joshi A, Kennedy AR, Kim AI, Lara K, Lee J, Li J, Lougheed JC, Ma S, Malek S, Manalo JC, Martini JF, McGrath G, Nicoll M, Nuss JM, Pack M, Peto CJ, Tsang TH, Wang L, Womble SW, Yakes M, Zhang W, Rice KD.
Abstract : With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
|
Antiproliferative activity against human HCT116 cells assessed as inhibition of cell viability after 48 hrs by MTT assay
|
Homo sapiens
|
780.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold.
Year : 2014
Volume : 24
Issue : 6
First Page : 1557
Last Page : 1561
Authors : Jia JM, Liu F, Xu XL, Guo XK, Jiang F, Cherfaoui B, Sun HP, You QD.
Abstract : Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel Hsp90 inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated. The structure-activity relationships (SAR) for these compounds was also discussed for further molecular design. This effort afforded the most active inhibitor 13f with improved activity in not only target-based level, but also cell-based level compared with the original hit 1.
|
Antiproliferative activity against human MCF7 cells assessed as inhibition of cell viability after 48 hrs by MTT assay
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold.
Year : 2014
Volume : 24
Issue : 6
First Page : 1557
Last Page : 1561
Authors : Jia JM, Liu F, Xu XL, Guo XK, Jiang F, Cherfaoui B, Sun HP, You QD.
Abstract : Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel Hsp90 inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated. The structure-activity relationships (SAR) for these compounds was also discussed for further molecular design. This effort afforded the most active inhibitor 13f with improved activity in not only target-based level, but also cell-based level compared with the original hit 1.
|
Inhibition of full-length Hsp90-ATPase activity (unknown origin) assessed as inhibition of ATP hydrolysis by spectrophotometry
|
Homo sapiens
|
930.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold.
Year : 2014
Volume : 24
Issue : 6
First Page : 1557
Last Page : 1561
Authors : Jia JM, Liu F, Xu XL, Guo XK, Jiang F, Cherfaoui B, Sun HP, You QD.
Abstract : Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel Hsp90 inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated. The structure-activity relationships (SAR) for these compounds was also discussed for further molecular design. This effort afforded the most active inhibitor 13f with improved activity in not only target-based level, but also cell-based level compared with the original hit 1.
|
Inhibition of HSP90 (unknown origin)-mediated ATPase activity at 40 uM after 3 hrs by malachite green assay relative to control
|
Homo sapiens
|
88.31
%
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Displacement of FITC-geldanamycin from HSP90 (unknown origin) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
90.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Antiproliferative activity against human MCF7 cells after 48 hrs by MTT assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Antiproliferative activity against human A231 cells after 48 hrs by MTT assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Drug metabolism in human liver microsomes assessed as 1 uM CYP3A inhibitor ketoconazole-mediated inhibition of (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(2-(dimethylamino)ethylamino)-13-hydroxy-10-(hydroxymethyl)-8,14-dimethoxy-4,12,16-trimethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate formation at 1 uM 17-DMAG by liquid chromatography-tandem mass spectrometry
|
Homo sapiens
|
75.0
%
|
|
Journal : Drug Metab. Dispos.
Title : In vitro metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin in human liver microsomes.
Year : 2011
Volume : 39
Issue : 4
First Page : 627
Last Page : 635
Authors : Zheng N, Zou P, Wang S, Sun D.
Abstract : The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.
|
Drug metabolism in human liver microsomes assessed as 1 uM CYP3A inhibitor ketoconazole-mediated inhibition of (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(2-(dimethylamino)-1-hydroxyethylamino)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate formation at 1 uM 17-DMAG by liquid chromatography-tandem mass spectrometry
|
Homo sapiens
|
77.0
%
|
|
Journal : Drug Metab. Dispos.
Title : In vitro metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin in human liver microsomes.
Year : 2011
Volume : 39
Issue : 4
First Page : 627
Last Page : 635
Authors : Zheng N, Zou P, Wang S, Sun D.
Abstract : The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.
|
Drug metabolism in human liver microsomes assessed as 1 uM CYP3A inhibitor ketoconazole-mediated inhibition of (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(2-(dimethylamino)ethylamino)-13,14-dihydroxy-8-methoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate formation at 1 uM 17-DMAG by liquid chromatography-tandem mass spectrometry
|
Homo sapiens
|
79.0
%
|
|
Journal : Drug Metab. Dispos.
Title : In vitro metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin in human liver microsomes.
Year : 2011
Volume : 39
Issue : 4
First Page : 627
Last Page : 635
Authors : Zheng N, Zou P, Wang S, Sun D.
Abstract : The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.
|
Drug metabolism in human liver microsomes assessed as 1 uM CYP3A inhibitor ketoconazole-mediated inhibition of (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(2-(dimethylamino)ethylamino)-8,13-dihydroxy-14-methoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate formation at 1 uM 17-DMAG by liquid chromatography-tandem mass spectrometry
|
Homo sapiens
|
81.0
%
|
|
Journal : Drug Metab. Dispos.
Title : In vitro metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin in human liver microsomes.
Year : 2011
Volume : 39
Issue : 4
First Page : 627
Last Page : 635
Authors : Zheng N, Zou P, Wang S, Sun D.
Abstract : The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.
|
Drug metabolism in human liver microsomes assessed as 1 uM CYP3A inhibitor ketoconazole-mediated inhibition of (4E,6Z,8S,9S,10E,12R,13R,14S,16R)-19-(2-(dimethylamino)-1-hydroxyethylamino)-13-hydroxy-12,16-bis(hydroxymethyl)-8,14-dimethoxy-4,10-dimethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate formation at 1 uM 17-DMAG by liquid chromatography-tandem mass spectrometry
|
Homo sapiens
|
83.0
%
|
|
Journal : Drug Metab. Dispos.
Title : In vitro metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin in human liver microsomes.
Year : 2011
Volume : 39
Issue : 4
First Page : 627
Last Page : 635
Authors : Zheng N, Zou P, Wang S, Sun D.
Abstract : The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced GSH. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not metabolized primarily through the reduction of benzoquinone and GSH conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-0.7
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of Hsp90 in human SKBR3 cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : J Med Chem
Title : Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.
Year : 2016
Volume : 59
Issue : 12
First Page : 5563
Last Page : 5586
Authors : Wang M, Shen A, Zhang C, Song Z, Ai J, Liu H, Sun L, Ding J, Geng M, Zhang A.
Abstract : Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.
|
Cytotoxicity against HGF-induced erlotinib-resistant human PC9 cells assessed as inhibition of cell growth after 72 hrs by MTT assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.
Year : 2016
Volume : 59
Issue : 12
First Page : 5563
Last Page : 5586
Authors : Wang M, Shen A, Zhang C, Song Z, Ai J, Liu H, Sun L, Ding J, Geng M, Zhang A.
Abstract : Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.
|
Cytotoxicity against HGF-induced erlotinib-resistant human Ma1 cells assessed as inhibition of cell growth after 72 hrs by MTT assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.
Year : 2016
Volume : 59
Issue : 12
First Page : 5563
Last Page : 5586
Authors : Wang M, Shen A, Zhang C, Song Z, Ai J, Liu H, Sun L, Ding J, Geng M, Zhang A.
Abstract : Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.
|
Inhibition of 6x-His tagged human recombinant full length Hsp90alpha ATPase preincubated for 0.5 hrs followed by ATP addition measured after 30 mins by HTRF assay
|
Homo sapiens
|
919.0
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity.
Year : 2016
Volume : 24
Issue : 19
First Page : 4626
Last Page : 4635
Authors : Xu X, Wu Y, Hu M, Li X, Gu C, You Q, Zhang X.
Abstract : Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure-activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.91
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.6
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.32
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.33
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.33
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.32
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
