|
Displacement of [3H]R1881 from AR in human LNCaP cells after 2 hrs by scintillation counting analysis
|
Homo sapiens
|
915.0
nM
|
|
Journal : J. Med. Chem.
Title : Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.
Year : 2013
Volume : 56
Issue : 12
First Page : 4880
Last Page : 4898
Authors : Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, Ramalingam S, Ates-Alagoz Z, Njar VC.
Abstract : As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.
|
Displacement of [3H]R1881 from AR in human MDA-MB-453 cells
|
Homo sapiens
|
49.0
nM
|
|
Journal : J. Med. Chem.
Title : Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.
Year : 2013
Volume : 56
Issue : 12
First Page : 4880
Last Page : 4898
Authors : Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, Ramalingam S, Ates-Alagoz Z, Njar VC.
Abstract : As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.
|
Antiproliferative activity against human LNCAP cells after 3 days
|
Homo sapiens
|
127.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.
Year : 2015
Volume : 99
First Page : 51
Last Page : 66
Authors : Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Vorobiev AA, Kuznetsova IV, Shevkun NA, Koryakova AG, Karapetian RN, Trifelenkov AS, Kravchenko DV, Veselov MS, Chufarova NV.
Abstract : A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.
|
Antagonist activity at androgen receptor (unknown origin)
|
Homo sapiens
|
28.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.
Year : 2015
Volume : 99
First Page : 51
Last Page : 66
Authors : Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Vorobiev AA, Kuznetsova IV, Shevkun NA, Koryakova AG, Karapetian RN, Trifelenkov AS, Kravchenko DV, Veselov MS, Chufarova NV.
Abstract : A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.
|
Antagonist activity at GAL4 DBD-fused androgen receptor LBD (unknown origin) transfected in UAS-bla GripTite 293 cells assessed as inhibition of R1881-induced receptor activation at 10 uM after 16 to 24 hrs by beta-lactamase reporter gene assay
|
Homo sapiens
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety.
Year : 2016
Volume : 26
Issue : 15
First Page : 3636
Last Page : 3640
Authors : Ferla S, Bassetto M, Pertusati F, Kandil S, Westwell AD, Brancale A, McGuigan C.
Abstract : Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.
|
Antagonist activity at GAL4 DBD-fused androgen receptor LBD (unknown origin) transfected in UAS-bla GripTite 293 cells assessed as inhibition of R1881-induced receptor activation after 16 to 24 hrs by beta-lactamase reporter gene assay
|
Homo sapiens
|
361.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety.
Year : 2016
Volume : 26
Issue : 15
First Page : 3636
Last Page : 3640
Authors : Ferla S, Bassetto M, Pertusati F, Kandil S, Westwell AD, Brancale A, McGuigan C.
Abstract : Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.
|
Displacement of [18F]-FDHT from androgen receptor in human LNCAP/AR cells
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.
Year : 2016
Volume : 26
Issue : 21
First Page : 5222
Last Page : 5228
Authors : Jadhavar PS, Ramachandran SA, Riquelme E, Gupta A, Quinn KP, Shivakumar D, Ray S, Zende D, Nayak AK, Miglani SK, Sathe BD, Raja M, Farias O, Alfaro I, Belmar S, Guerrero J, Bernales S, Chakravarty S, Hung DT, Lindquist JN, Rai R.
Abstract : While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356μM and AR binding IC50=<0.03μM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.
|
Displacement of fluormone-DHT green from His/GST-tagged rat AR ligand binding domain after 4 to 8 hrs by fluorescence polarization assay
|
Rattus norvegicus
|
294.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Identification of Triptophenolide from Tripterygium wilfordii as a Pan-antagonist of Androgen Receptor.
Year : 2016
Volume : 7
Issue : 12
First Page : 1024
Last Page : 1027
Authors : He Y, Wu M, Liu Y, Li Q, Li X, Hu L, Cen S, Zhou J.
Abstract : A compound, triptophenolide, derived from Tripterygium wilfordii was identified as an antiandrogen. Triptophenolide inhibits the activity of both wild-type and F876L mutant androgen receptors. Triptophenolide exhibits its antiandrogenic activity through competitive binding with androgen in the hormone-binding pocket, decreasing the expression of androgen receptor, and reducing the nuclear translocation of androgen receptor.
|
Antagonist activity at androgen receptor (unknown origin) expressed in COS-7 cells assessed as inhibition of R1881-induced MMTV promoter activity at 10 uM by luciferase reporter gene assay relative to control
|
Homo sapiens
|
86.5
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of indoline thiohydantoin derivatives based on enzalutamide as antiproliferative agents against prostate cancer.
Year : 2017
Volume : 125
First Page : 1002
Last Page : 1022
Authors : Zuo M, Xu X, Xie Z, Ge R, Zhang Z, Li Z, Bian J.
Abstract : A novel scaffold of indoline thiohydantoin was discovered as potent androgen receptor (AR) antagonist through rational drug designation. Several compounds showed good biological profiles in AR binding and higher selective toxicity than enzalutamide toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient). In addition, the docking studies supported the rationalization of the biological evaluation. Among these compounds, the representative compound 48c exhibited the strongest inhibitory effect on LNCaP growth and also acted as a competitive AR antagonist. Further preliminary mechanism study confirmed that 48c exerted its AR antagonistic activity through impairing AR nuclear translocation. All these results indicated that the novel scaffold compounds demonstrated AR antagonistic behavior and promising candidates for future development were identified.
|
Antagonist activity at full length human androgen receptor expressed in mammalian expression system measured after 22 to 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
420.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer.
Year : 2017
Volume : 27
Issue : 10
First Page : 2216
Last Page : 2220
Authors : Salvino JM, Srikanth YVV, Lou R, Oyer HM, Chen N, Kim FJ.
Abstract : Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2-3years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach.
|
Antagonist activity at androgen receptor (unknown origin) expressed in African green monkey COS7 cells assessed as inhibition of R1881-induced protein activation at 10 uM after 24 hrs by luciferase reporter gene assay relative to control
|
Homo sapiens
|
86.5
%
|
|
Journal : Eur J Med Chem
Title : Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents.
Year : 2018
Volume : 143
First Page : 1325
Last Page : 1344
Authors : Xu X, Ge R, Li L, Wang J, Lu X, Xue S, Chen X, Li Z, Bian J.
Abstract : Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.
|
Inhibition of R1881-induced full length AR transcriptional activity in human LNCAP cells harboring AR2PB-eGFP construct after 72 hrs by fluorescence assay
|
Homo sapiens
|
90.0
nM
|
|
Journal : Eur J Med Chem
Title : Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor.
Year : 2018
Volume : 157
First Page : 1164
Last Page : 1173
Authors : Dalal K, Morin H, Ban F, Shepherd A, Fernandez M, Tam KJ, Li H, LeBlanc E, Lack N, Prinz H, Rennie PS, Cherkasov A.
Abstract : The androgen receptor (AR) is a hormone-activated transcription factor that regulates the development and progression of prostate cancer (PCa) and represents one of the most well-established drug targets. Currently clinically approved small molecule inhibitors of AR, such as enzalutamide, are built upon a common chemical scaffold that interacts with the AR by the same mechanism of action. These inhibitors eventually fail due to the emergence of drug-resistance in the form of AR mutations and expression of truncated AR splice variants (e.g. AR-V7) that are constitutively active, signalling the progression of the castration-resistant state of the disease. The urgent need therefore continues for novel classes of AR inhibitors that can overcome drug resistance, especially since AR signalling remains important even in late-stage advanced PCa. Previously, we identified a collection of 10-benzylidene-10H-anthracen-9-ones that effectively inhibit AR transcriptional activity, induce AR degradation and display some ability to block recruitment of hormones to the receptor. In the current work, we extended the analysis of the lead compounds, and used methods of both ligand- and structure-based drug design to develop a panel of novel 10-benzylidene-10H-anthracen-9-one derivatives capable of suppressing transcriptional activity and protein expression levels of both full length- and AR-V7 truncated forms of human androgen receptor. Importantly, the developed compounds efficiently inhibited the growth of AR-V7 dependent prostate cancer cell-lines which are completely resistant to all current anti-androgens.
|
Inhibition of full length AR transcriptional activity in human LNCAP cells harboring AR2PB-eGFP construct assessed as reduction in R1881-induced secreted PSA level after 72 hrs by fluorescence assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor.
Year : 2018
Volume : 157
First Page : 1164
Last Page : 1173
Authors : Dalal K, Morin H, Ban F, Shepherd A, Fernandez M, Tam KJ, Li H, LeBlanc E, Lack N, Prinz H, Rennie PS, Cherkasov A.
Abstract : The androgen receptor (AR) is a hormone-activated transcription factor that regulates the development and progression of prostate cancer (PCa) and represents one of the most well-established drug targets. Currently clinically approved small molecule inhibitors of AR, such as enzalutamide, are built upon a common chemical scaffold that interacts with the AR by the same mechanism of action. These inhibitors eventually fail due to the emergence of drug-resistance in the form of AR mutations and expression of truncated AR splice variants (e.g. AR-V7) that are constitutively active, signalling the progression of the castration-resistant state of the disease. The urgent need therefore continues for novel classes of AR inhibitors that can overcome drug resistance, especially since AR signalling remains important even in late-stage advanced PCa. Previously, we identified a collection of 10-benzylidene-10H-anthracen-9-ones that effectively inhibit AR transcriptional activity, induce AR degradation and display some ability to block recruitment of hormones to the receptor. In the current work, we extended the analysis of the lead compounds, and used methods of both ligand- and structure-based drug design to develop a panel of novel 10-benzylidene-10H-anthracen-9-one derivatives capable of suppressing transcriptional activity and protein expression levels of both full length- and AR-V7 truncated forms of human androgen receptor. Importantly, the developed compounds efficiently inhibited the growth of AR-V7 dependent prostate cancer cell-lines which are completely resistant to all current anti-androgens.
|
Antagonist activity at alpha1 androgen receptor (unknown origin) assessed as reduction in R1881-induced response at 10 uM by dual-luciferase reporter gene assay relative to control
|
Homo sapiens
|
84.7
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents.
Year : 2019
Volume : 27
Issue : 1
First Page : 133
Last Page : 143
Authors : Chen H, Yu YZ, Tian XM, Wang CL, Qian YN, Deng ZA, Zhang JX, Lv DJ, Zhang HB, Shen JL, Yuan M, Zhao SC.
Abstract : A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.
|
Antiproliferative activity against AR-positive human LNCAP cells incubated for 7 days in presence of AR agonist, R1881 by WST-8 assay
|
Homo sapiens
|
150.8
nM
|
|
Journal : J Med Chem
Title : Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands.
Year : 2019
Volume : 62
Issue : 24
First Page : 11218
Last Page : 11231
Authors : Han X, Zhao L, Xiang W, Qin C, Miao B, Xu T, Wang M, Yang CY, Chinnaswamy K, Stuckey J, Wang S.
Abstract : Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of <b>11</b> (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC<sub>50</sub> values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.
|
Antiproliferative activity against AR- positive human VCaP cells incubated for 7 days in presence of AR agonist, R1881 by WST-8 assay
|
Homo sapiens
|
364.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands.
Year : 2019
Volume : 62
Issue : 24
First Page : 11218
Last Page : 11231
Authors : Han X, Zhao L, Xiang W, Qin C, Miao B, Xu T, Wang M, Yang CY, Chinnaswamy K, Stuckey J, Wang S.
Abstract : Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of <b>11</b> (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC<sub>50</sub> values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.
|
Antiproliferative activity against human LNCaP-AR cells assessed as reduction in cell viability incubated for 6 days by CCK8 assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer.
Year : 2019
Volume : 171
First Page : 265
Last Page : 281
Authors : Yu J, Zhang L, Yan G, Zhou P, Cao C, Zhou F, Li X, Chen Y.
Abstract : Prostate cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective androgen receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.
|
Antiproliferative activity against human VCaP cells assessed as reduction in cell viability at 30 uM incubated for 6 days by CCK8 assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer.
Year : 2019
Volume : 171
First Page : 265
Last Page : 281
Authors : Yu J, Zhang L, Yan G, Zhou P, Cao C, Zhou F, Li X, Chen Y.
Abstract : Prostate cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective androgen receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.
|
Inhibition of R1881 induced-AR transcriptional activity in AR-positive human 22Rv1 cells harboring ARE14 construct at 10 uM after 24 hrs by luciferase assay relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel galeterone derivatives and evaluation of their in vitro activity against prostate cancer cell lines.
Year : 2019
Volume : 179
First Page : 483
Last Page : 492
Authors : Jorda R, Řezníčková E, Kiełczewska U, Maj J, Morzycki JW, Siergiejczyk L, Bazgier V, Berka K, Rárová L, Wojtkielewicz A.
Abstract : Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.
|
Antiproliferative activity against human LNCAP expressing AR assessed as reduction in cell viability incubated for 6 days by CCK-8 assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants.
Year : 2019
Volume : 182
First Page : 111608
Last Page : 111608
Authors : Yu J, Zhou P, Hu M, Yang L, Yan G, Xu R, Deng Y, Li X, Chen Y.
Abstract : Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.
|
Antiproliferative activity against human VCaP expressing AR assessed as reduction in cell viability at 30 uM incubated for 6 days by CCK-8 assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants.
Year : 2019
Volume : 182
First Page : 111608
Last Page : 111608
Authors : Yu J, Zhou P, Hu M, Yang L, Yan G, Xu R, Deng Y, Li X, Chen Y.
Abstract : Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.
|
Antagonist activity at androgen receptor (unknown origin) assessed as inhibition of R1881-induced receptor transactivation at 10 uM by dual-luciferase reporter gene assay relative to control
|
Homo sapiens
|
84.7
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, biological evaluation and molecular docking of 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs containing the piperazine moiety.
Year : 2019
Volume : 27
Issue : 20
First Page : 115081
Last Page : 115081
Authors : Chen H, Zhang J, Hu P, Qian Y, Li J, Shen J.
Abstract : Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.
|
Antagonist activity at human androgen receptor expressed in HEK293 cells assessed as inhibition of R1881-induced receptor transactivation after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
216.0
nM
|
|
Journal : J Med Chem
Title : New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity.
Year : 2019
Volume : 62
Issue : 2
First Page : 491
Last Page : 511
Authors : Hwang DJ, He Y, Ponnusamy S, Mohler ML, Thiyagarajan T, McEwan IJ, Narayanan R, Miller DD.
Abstract : In our effort to find small-molecule treatments of advanced prostate cancers (PCs), a novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration-resistant, Enz-R, and/or AR SV-dependent advanced PCs that are often untreatable with known hormone therapies are discussed.
|
Antagonist activity at rat androgen receptor fused with DNA-binding domain of GAL4 expressed in AR-UAS-bla GripTite 293 cells assessed as inhibition of R1881-induced receptor activation at 10 uM preincubated for 30 mins followed by R1881 addition measured after 16 to 24 hrs by betalactamase reporter gene assay relative to control
|
Rattus norvegicus
|
95.0
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer.
Year : 2016
Volume : 118
Issue : NULL
First Page : 230
Last Page : 243
Authors : Bassetto M, Ferla S, Pertusati F, Kandil S, Westwell AD, Brancale A, McGuigan C.
Abstract : Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
|
Antagonist activity at rat androgen receptor fused with DNA-binding domain of GAL4 expressed in AR-UAS-bla GripTite 293 cells assessed as inhibition of R1881-induced receptor activation preincubated for 30 mins followed by R1881 addition measured after 16 to 24 hrs by betalactamase reporter gene assay
|
Rattus norvegicus
|
361.0
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer.
Year : 2016
Volume : 118
Issue : NULL
First Page : 230
Last Page : 243
Authors : Bassetto M, Ferla S, Pertusati F, Kandil S, Westwell AD, Brancale A, McGuigan C.
Abstract : Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
|
Inhibition of DHT-induced androgen receptor transactivation in human LNCaP cells after 24 hrs by luciferase reporter gene assay relative to control
|
Homo sapiens
|
180.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Identification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate.
Year : 2016
Volume : 7
Issue : 7
First Page : 708
Last Page : 713
Authors : Purushottamachar P, Kwegyir-Afful AK, Martin MS, Ramamurthy VP, Ramalingam S, Njar VC.
Abstract : Degradation of all forms of androgen receptors (ARs) is emerging as an advantageous therapeutic paradigm for the effective treatment of prostate cancer. In continuation of our program to identify and develop improved efficacious novel small-molecule agents designed to disrupt AR signaling through enhanced AR degradation, we have designed, synthesized, and evaluated novel C-3 modified analogues of our phase 3 clinical agent, galeterone (5). Concerns of potential in vivo stability of our recently discovered more efficacious galeterone 3β-imidazole carbamate (6) led to the design and synthesis of new steroidal compounds. Two of the 11 compounds, 3β-pyridyl ether (8) and 3β-imidazole (17) with antiproliferative GI50 values of 3.24 and 2.54 μM against CWR22Rv1 prostate cancer cell, are 2.75- and 3.5-fold superior to 5. In addition, compounds 8 and 17 possess improved (∼4-fold) AR-V7 degrading activities. Importantly, these two compounds are expected to be metabolically stable, making them suitable for further development as new therapeutics against all forms of prostate cancer.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.87
%
|
|
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
|
0.02
%
|
|
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
|
0.02
%
|
|
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.
|
Antagonist activity at recombinant human AR expressed in HEK293 cells assessed as inhibition of R1881-induced transcriptional activity measured after 24 hrs by dual luciferase reporter gene assay
|
Homo sapiens
|
216.0
nM
|
|
Journal : J Med Chem
Title : Pyrazol-1-yl-propanamides as SARD and Pan-Antagonists for the Treatment of Enzalutamide-Resistant Prostate Cancer.
Year : 2020
Volume : 63
Issue : 21
First Page : 12642
Last Page : 12665
Authors : He Y,Hwang DJ,Ponnusamy S,Thiyagarajan T,Mohler ML,Narayanan R,Miller DD
Abstract : We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring-linkage-B-ring nonsteroidal antiandrogens' general pharmacophore allowed the development of a new scaffold of small molecules with unique SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-155 (9) and UT-34 (10). Novel B-ring pyrazoles exhibited potent AR antagonist activities, including promising distribution, metabolism, and pharmacokinetic properties, and broad-spectrum AR antagonist properties, including potent in vivo antitumor activity. 26a was able to induce an 80% tumor growth inhibition of xenografts derived from the enzalutamide-resistant (Enz-R) VCaP cell line. These results represent an advancement toward the development of novel AR antagonists for the treatment of Enz-R prostate cancer.
|
Antagonist activity at androgen receptor in human LNCaP cells transfected with ARR2 PB-eGFP assessed as inhibition of DHT-induced transcriptional activity measured after 3 days by fluorescence assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation.
Year : 2020
Volume : 192
First Page : 112156
Last Page : 112156
Authors : Tang Q,Fu W,Zhang M,Wang E,Shan L,Chai X,Pang J,Wang X,Xu X,Xu L,Li D,Sheng R,Hou T
Abstract : Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC of 2.4 μM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.
|
Inhibition of prostate specific antigen in human LNCaP cells
|
Homo sapiens
|
130.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation.
Year : 2020
Volume : 192
First Page : 112156
Last Page : 112156
Authors : Tang Q,Fu W,Zhang M,Wang E,Shan L,Chai X,Pang J,Wang X,Xu X,Xu L,Li D,Sheng R,Hou T
Abstract : Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC of 2.4 μM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.
|
Antagonist activity at Androgen receptor (unknown origin) expressed in COS7 cells at 1 uM by dual luciferase reporter gene assay relative to control
|
Homo sapiens
|
84.7
%
|
|
Journal : Eur J Med Chem
Title : Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists.
Year : 2020
Volume : 192
First Page : 112196
Last Page : 112196
Authors : Xu X,Du Q,Meng Y,Li Z,Wu H,Li Y,Zhao Z,Ge R,Lu X,Xue S,Chen X,Yang Y,Wang J,Bian J
Abstract : Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.
|
Antagonist activity at androgen receptor (unknown origin) expressed in HEK293 cells using DHT as substrate preincubated for 30 mins followed by substrate addition measured after 24 hrs by Steady-Glo luciferase assay
|
Homo sapiens
|
646.9
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer.
Year : 2021
Volume : 31
First Page : 115953
Last Page : 115953
Authors : Wang A,Wang Y,Meng X,Yang Y
Abstract : Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3-fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.
|
Antiproliferative activity against AR overexpressing human LNCaP/AR cells assessed as reduction in cell proliferation measured after 6 days by CellTiter-Glo assay
|
Homo sapiens
|
730.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer.
Year : 2021
Volume : 31
First Page : 115953
Last Page : 115953
Authors : Wang A,Wang Y,Meng X,Yang Y
Abstract : Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3-fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.
|
Inhibition of androgen receptor (unknown origin)
|
Homo sapiens
|
86.0
nM
|
|
Inhibition of androgen receptor (unknown origin)
|
Homo sapiens
|
219.0
nM
|
|
Journal : Eur J Med Chem
Title : New drug approvals for 2019: Synthesis and clinical applications.
Year : 2020
Volume : 205
First Page : 112667
Last Page : 112667
Authors : Yuan S,Yu B,Liu HM
Abstract : 48 new drugs including 38 chemical entities (33 new chemical entities, 3 new diagnostic agents, and 2 payloads of antibody drug conjugates) and 10 biologics were approved by the U.S. Food and Drug Administration (FDA) during 2019. These marketed new drugs represent privileged structures and novel action of mechanism, and thus can be served as leads to discover new drugs with the similar biological targets and improved therapeutic efficacy. This review aims to provide an overview regarding the synthetic approaches of 33 new chemical entities approved by the FDA in 2019 and their clinical applications.
|
Antiproliferative activity against human VCaP cells assessed as reduction in cell viability at 33 uM incubated for 144 hrs by cell-titer glo assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC).
Year : 2018
Volume : 61
Issue : 7.0
First Page : 3037
Last Page : 3058
Authors : Zhang M,Zhang Y,Song M,Xue X,Wang J,Wang C,Zhang C,Li C,Xiang Q,Zou L,Wu X,Wu C,Dong B,Xue W,Zhou Y,Chen H,Wu D,Ding K,Xu Y
Abstract : The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[ d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with K values of 82 and 81 nM, respectively. They also exhibited high selectivity over other non-BET subfamily members. The compounds potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate cancer cell lines. Compounds 6i and 7m also demonstrated therapeutic effects in a C4-2B CRPC xenograft tumor model in mice. These potent and selective BET inhibitors represent a new class of compounds for the development of potential therapeutics against CRPC.
|
Antagonist activity at human androgen receptor expressed in HEK-293 cells harboring GRE-LUC and CMV-renilla luciferase assessed as inhibition of transactivation incubated for 24 hrs in presence of R1881 by dual luciferase assay
|
Homo sapiens
|
216.0
nM
|
|
|
Antagonist activity at androgen receptor (unknown origin) transfected in COS7 cells cotransfected with pMMTV-LUC vector and pRL-SV4 assessed as inhibition of AR transcriptional activity at 10 uM incubated for 24 hrs by dual luciferase reporter gene assay relative to control
|
Homo sapiens
|
85.5
%
|
|
|
Displacement of [3H]methyltrienolone from wild-type androgen receptor in human LNCaP cells incubated for 24 hrs by scintillation counting analysis
|
Homo sapiens
|
38.0
nM
|
|
|
Binding affinity to wild-type androgen receptor in human LNCaP cells assessed as inhibition constant incubated for 24 hrs by Cheng-Prusoff equation analysis
|
Homo sapiens
|
17.0
nM
|
|
|
Agonist activity at VP16-AR F877L mutant (unknown origin) transfected in human HepG2 cells cotransfected with ARE-LUC incubated for 48 hrs by steady-glo luciferase reporter gene assay
|
Homo sapiens
|
61.8
nM
|
|
|
Antagonist activity at AR wild-type (unknown origin) transfected in human LNCAP cells cotransfected with ARE-LUC incubated for 20 to 24 hrs in presence of AR agonist R1881 by steady-glo luciferase reporter gene assay
|
Homo sapiens
|
117.0
nM
|
|
|
Antiproliferative activity against human VCaP cells expressing wild-type androgen receptor assessed as reduction in cell viability incubated for 5 days in presence of R1881 by CellTiter-glo assay
|
Homo sapiens
|
149.0
nM
|
|
|
Antagonist activity at androgen receptor in human LNCaP cells harboring eGFP/ARRIPB incubated for 3 days by fluorescence method
|
Homo sapiens
|
75.0
nM
|
|
|
Antagonist activity at wild type androgen receptor in castration-resistant human LNCaP cells assessed as inhibition of R1881-stimulated receptor transcriptional activation measured after 20 to 24 hrs by Steady-Glo luciferase assay
|
Homo sapiens
|
117.0
nM
|
|
|
Antiproliferative activity against human VCaP cells expressing wild type AR assessed as reduction in R1881-stimulated cell proliferation measured after 5 days by Celltiter-Glo luminescence assay
|
Homo sapiens
|
149.0
nM
|
|
|
Growth inhibition of human VCaP cells assessed as cell viability measured after 4 days in presence of R1881 by WST-8 assay
|
Homo sapiens
|
394.0
nM
|
|
|
Growth inhibition of human LNCaP cells assessed as cell viability measured after 4 days in presence of R1881 by WST-8 assay
|
Homo sapiens
|
133.0
nM
|
|
|
Growth inhibition of human VCaP cells assessed as cell viability by WST-8 assay
|
Homo sapiens
|
393.0
nM
|
|
|
Growth inhibition of human LNCaP cells carrying AR T878A mutant assessed as cell viability by WST-8 assay
|
Homo sapiens
|
133.0
nM
|
|
|
Antagonist activity against human androgen receptor expressed in human LNCap cells trasfected with ARR2PB-eGFP cells incubated for 3 days by fluorescence based AR transcription assay
|
Homo sapiens
|
70.0
nM
|
|
|
Inhibition of prostate specific antigen expression in human LNCaP cells expressing ARR2PB-eGFP by immunoassay
|
Homo sapiens
|
100.0
nM
|
|
|
Binding affinity to GST-tagged AR ligand binding domain (unknown origin) measured after 4 hrs by fluorescence polarization assay
|
Homo sapiens
|
80.0
nM
|
|
|
Inhibition of AR transcriptional activity in human LNCaP cells harboring ARR2PB-eGFP incubated for 72 hrs by fluorescence assay
|
Homo sapiens
|
14.0
nM
|
|
|
Inhibition of AR transcriptional activity in human LNCaP cells harboring ARR2PB-eGFP assessed as decrease in PSA level
|
Homo sapiens
|
480.0
nM
|
|
