Lyase Inhibitor

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William R. Moore - One of the best experts on this subject based on the ideXlab platform.

  • Abstract P3-14-04: Effects of the dual selective CYP17 Lyase Inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo
    Poster Session Abstracts, 2016
    Co-Authors: Stephanie J. Ellison, Joel R. Eisner, William R. Moore, John D. Norris, Suzanne E. Wardell, William J. Hoekstra, David B. Stagg, Holly M. Alley, Donald P. Mcdonnell
    Abstract:

    VT-464 is a Lyase-selective Inhibitor of the dual-activity CYP17A1 enzyme that is required for the synthesis of androgens and estrogens in the gonads, adrenals, and tumors. In addition to its role as a CYP17A1 Lyase Inhibitor, we previously showed that VT-464 also functions as a direct and effective AR antagonist in prostate cancer models. In our current study, we evaluated the therapeutic potential of VT-464 in breast cancer by analyzing its effectiveness in several AR-positive breast cancer cell lines, including those that are ER-positive and ER-negative. Through in vitro assays and xenograft analysis, we compared the activity of VT-464 to enzalutamide, a second generation AR antagonist that is approved for the treatment of castration resistant prostate cancer and is in multiple Phase 2 breast cancer studies. Our results showed that VT-464 was highly effective in preventing proliferation of both ER-positive and ER-negative breast cancer cell lines in vitro. Importantly, significant inhibition was also observed in soft agar assays that assesses anchorage-independent growth. In mechanistic studies, VT-464 and enzalutamide both inhibited induction of AR target genes and recruitment of AR to target promoters, verifying direct AR antagonistic activity observed previously in prostate cancer cells. Furthermore, we evaluated the ability of VT-464 and enzalutamide to inhibit tumor formation in a tamoxifen-resistant model of breast cancer. Oral administration of either enzalutamide or VT-464 significantly decreased tumor growth in mice, with VT-464 achieving greater growth inhibition than enzalutamide. Together, these data provide further rationale for the future study of the AR as a viable therapeutic target in breast cancer, and importantly, suggest that AR inhibition can impact tamoxifen-resistant tumor growth. The dual effects of CYP17A1 Lyase inhibition and AR antagonism that are achieved with VT-464 further supports its development as an effective oral therapy option for AR-positive breast cancer. A phase 1 / 2 clinical study of oral VT-464 in women with AR+ triple-negative breast cancer or ER+ cancer resistant to aromatase Inhibitors will commence in 2015. Citation Format: Ellison SJ, Norris JD, Wardell S, Eisner JR, Hoekstra WJ, Stagg DB, Alley HM, Moore WR, McDonnell DP. Effects of the dual selective CYP17 Lyase Inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-04.

  • The enzymology of the selective CYP17 Lyase Inhibitor, VT-464, and its effects in castration-resistant prostate cancer (CRPC) models.
    Journal of Clinical Oncology, 2014
    Co-Authors: William R. Moore, Joel R. Eisner, William J. Hoekstra, Eleni Efstathiou, Sankar N. Maity, Edward P. Garvey, Mark Titus, Christopher J. Logothetis, John C. Araujo, Robert J. Schotzinger
    Abstract:

    158 Background: CRPC typically responds to anti-androgen therapy but resistance is common. CYP17 Inhibitors that block Lyase (L) and not hydroxylase (H), do not require prednisone, and may delay tumor resistance are needed. VT-464 is an oral, non-steroidal Inhibitor of CYP17 L in clinical development for CRPC. The present studies characterized: 1) the kinetic mechanism of VT-464 inhibition of h-CYP17 L and H, and 2) VT-464 effects compared to abiraterone acetate (AA) in CRPC models. Methods: CYP17 Enzyme Assays: r-h-CYP17 inhibition studies were conducted using substrates pregnenolone (for H) or 17-a-hydroxypregnenolone (for L). Product rates (17-a-hydroxypregnenolone (H) and DHEA (L)) were assessed by LC/MS/MS. Data were fit to inhibition models using SigmaPlot 11.2. In vitro CRPC studies: VT-464 and AA effects on AR transcription (luciferase) and PSA and NKX3.1 gene expression (QRT-PCR) were compared in C4-2B cells. Mouse xenograft model: Effects of oral VT-464 or AA on tumor growth and tumoral steroids...

  • Activity of oral VT-464, a selective CYP17-Lyase Inhibitor, in the LNCaP prostate cancer xenograft
    Journal of Clinical Oncology, 2012
    Co-Authors: William D. Figg, Stephen T Pisle, Heather M. Pressler, Sarah M. Troutman, Joel R. Eisner, Stephen W. Rafferty, Robert J. Schotzinger, Shawn D. Spencer, William R. Moore
    Abstract:

    4671 Background: With the FDA approval of abiraterone acetate, inhibition of CYP17 (17α hydroxylase/C17, 20-Lyase) is now a validated approach to the treatment of castration-resistant prostate cancer. VT-464 is a novel, selective CYP17-Lyase Inhibitor with decreased activity against CYP17 hydroxylase (less mineralcocorticoid and glucocorticoid effects). The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100 mm3, mice were randomized to receive vehicle (0.5% CMC in saline, 5 mL/kg), VT-464 at 15, 50, or 100 mg/kg p.o. b.i.d. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464, or abiraterone acetate at 100 mg/kg p.o. b.i.d. for 28 days. Terminal blood and tumor concentrations were analyzed on day 28, four hours after the last dose. Results: In the first LNCaP xe...

  • Activity of VT-464, a selective CYP17 Lyase Inhibitor, in the LNCaP prostate cancer xenograft model.
    Journal of Clinical Oncology, 2012
    Co-Authors: Stephen T Pisle, Heather M. Pressler, Sarah M. Troutman, Joel R. Eisner, Stephen W. Rafferty, Robert J. Schotzinger, William R. Moore, William D. Figg
    Abstract:

    64 Background: With the recent FDA approval of abiraterone acetate, CYP17 (17α hydroxylase/C17, 20-Lyase) has become a proven target for the treatment of castration- resistant prostate cancer. Inhibition of CYP17-Lyase causes a decrease in circulating androgens, severely hampering activation of the androgen receptor signaling pathway that prostate cancer relies on for proliferation. However, inhibition of CYP17-hydroxylase, a second enzymatic activity of CYP17, leads to an increase in upstream steroids that can cause mineralocorticoid excess syndrome as well as a decrease in cortisol production. VT-464 is a novel, selective CYP17 Lyase Inhibitor with decreased activity against CYP17 hydroxylase. The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100mm3, mice were randomized to receive vehicle (0.5% CM...

Vincent C. O. Njar - One of the best experts on this subject based on the ideXlab platform.

  • 17α-Hydroxylase/17,20 Lyase Inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
    Molecular cancer therapeutics, 2008
    Co-Authors: Robert D. Bruno, Tony D. Gover, Angelika M. Burger, Angela Brodie, Vincent C. O. Njar
    Abstract:

    Inhibitors of the enzyme 17α-hydroxylase/17,20 Lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17α-hydroxylase/17,20 Lyase Inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 μmol/L and 7.55 μmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 μmol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 μmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]

  • 17α hydroxylase 17 20 Lyase Inhibitor vn 124 1 inhibits growth of androgen independent prostate cancer cells via induction of the endoplasmic reticulum stress response
    Molecular Cancer Therapeutics, 2008
    Co-Authors: Robert D. Bruno, Tony D. Gover, Angelika M. Burger, Angela Brodie, Vincent C. O. Njar
    Abstract:

    Inhibitors of the enzyme 17α-hydroxylase/17,20 Lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17α-hydroxylase/17,20 Lyase Inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 μmol/L and 7.55 μmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 μmol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 μmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]

  • Androgen receptor inactivation contributes to antitumor efficacy of 17A-hydroxylase/17,20-Lyase Inhibitor
    2008
    Co-Authors: Tadas S. Vasaitis, Vincent C. O. Njar, Aashvini Belosay, Adam Schayowitz, Aakanksha Khandelwal, Pankaj Chopra, Lalji K. Gediya, Zhiyong Guo, Hong-bin Fang, Angela Brodie
    Abstract:

    We previously reported that our novel compound 3Bhydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17A-hydroxylase/17,20-Lyase (CYP17) Inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 Inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm 3 in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/ 124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2348–57]

  • androgen receptor inactivation contributes to antitumor efficacy of 17a hydroxylase 17 20 Lyase Inhibitor
    2008
    Co-Authors: Tadas S. Vasaitis, Vincent C. O. Njar, Aashvini Belosay, Adam Schayowitz, Aakanksha Khandelwal, Pankaj Chopra, Lalji K. Gediya, Zhiyong Guo, Hong-bin Fang, Angela Brodie
    Abstract:

    We previously reported that our novel compound 3Bhydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17A-hydroxylase/17,20-Lyase (CYP17) Inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 Inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm 3 in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/ 124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2348–57]

Robert Dreicer - One of the best experts on this subject based on the ideXlab platform.

Tomohiro Kaku - One of the best experts on this subject based on the ideXlab platform.

  • Effect of a novel 17,20-Lyase Inhibitor, orteronel (TAK-700), on androgen synthesis in male rats
    The Journal of Steroid Biochemistry and Molecular Biology, 2013
    Co-Authors: Takahito Hara, Jin Kouno, Tomohiro Kaku, Toshiyuki Takeuchi, Masami Kusaka, Akihiro Tasaka, Masuo Yamaoka
    Abstract:

    Abstract Endogenous androgens play a role in the development and progression of prostate cancer (PC), thus androgen suppression may offer an effective therapeutic strategy for this disease. Orteronel (TAK-700), 6-[(7 S )-7-hydroxy-6,7-dihydro-5 H -pyrrolo[1,2- c ]imidazol-7-yl]- N -methyl-2-naphthamide, is a novel, non-steroidal, selective Inhibitor of the 17,20-Lyase activity of CYP17A – a key enzyme in the production of steroidal hormones – and is being developed as a therapy for PC. The purpose of this study was to elucidate the Inhibitory activity of orteronel, in particular its specificity for androgen synthesis enzymes, in male rats – an androgen-synthesis model that largely reflects this pathway in humans. Orteronel inhibited 17,20-Lyase activity in rats with an IC 50 of 1200 nM but did not inhibit 17α-hydroxylase or 11β-hydroxylase (CYP11B1) activity in rats at concentrations up to 10 μM. In cellular steroidogenesis assays using rat testicular cells, orteronel suppressed testosterone and androstenedione production with an IC 50 of 640 nM and 210 nM, respectively, but did not suppress either corticosterone or aldosterone production in rat adrenal cells at concentrations up to 30 μM. In addition, serum testosterone and androstenedione levels in human chorionic gonadotropin-injected hypophysectomized rats were significantly reduced by single oral administration of orteronel at a dose of 30 mg/kg (both p  ≤ 0.01); serum corticosterone and aldosterone levels in ACTH-injected hypophysectomized rats did not result in significant differences compared with controls, following orteronel administration at doses up to 300 mg/kg. Serum testosterone levels in intact male rats were significantly reduced by orteronel 4 h after dosing at 100 mg/kg ( p  ≤ 0.01); testosterone levels showed a tendency to recover afterward. In intact male rats, the weight of the prostate glands and seminal vesicles was decreased in a dose-dependent manner following multiple doses of orteronel at 37.5, 150, and 600 mg/kg, TID for 4 days. The reversibility of orteronel was further confirmed using a human adrenocortical tumor cell line. In summary, orteronel is a selective and reversible 17,20-Lyase Inhibitor, and decreases the weight of androgen-dependent organs in male rats. Our data suggests that orteronel would therefore be effective for androgen-dependent disorders such as PC.

  • orteronel tak 700 a novel non steroidal 17 20 Lyase Inhibitor effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys
    The Journal of Steroid Biochemistry and Molecular Biology, 2012
    Co-Authors: Masuo Yamaoka, Takahito Hara, Tomohiro Kaku, Toshiyuki Takeuchi, Akihiro Tasaka, Satoru Asahi, Takenori Hitaka, Junzo Takahashi, Hiroshi Miki, Masami Kusaka
    Abstract:

    Abstract Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the ‘castration resistant’ (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-Lyase and 17-hydroxylase catalytic activities with the 17,20-Lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent Inhibitor of 17,20-Lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the Inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC 50 value of orteronel for cortisol was ∼3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-Lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-Lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-Lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.

  • Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-Lyase Inhibitor with potential utility in the treatment of prostate cancer.
    Bioorganic & medicinal chemistry, 2011
    Co-Authors: Tomohiro Kaku, Takahito Hara, Masami Kusaka, Masuo Yamaoka, Akio Ojida, Nobuyuki Matsunaga, Takenori Hitaka, Mari Adachi, Toshimasa Tanaka, Teruaki Okuda
    Abstract:

    Abstract A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-Lyase Inhibitors. Based on the structure–activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-Lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-Lyase Inhibitor. Biological evaluation of (+)-3c at a dose of 1 mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.

  • Stereocontrolled synthesis of (1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-2-methylpropan-1-ol as a potent C17,20-Lyase Inhibitor
    Tetrahedron: Asymmetry, 2004
    Co-Authors: Akio Ojida, Tomohiro Kaku, Nobuyuki Matsunaga, Akihiro Tasaka
    Abstract:

    Abstract An efficient stereocontrolled synthesis of the potent C17,20-Lyase Inhibitor, (1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-2-methyl-1-propanol 1, has been established. The stereogenic center of 1 was successfully constructed by a highly diastereoselective Grignard reaction of 2, while a subsequent imidazole ring annulation afforded 1 in an enantiomerically pure form. The procedure enables a practical synthesis of 1 that can be conveniently carried out on a multigram scale.

  • Synthetic studies on (1S)-1-(6,7-dimethoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methylpropan-1-ol as a selective C17,20-Lyase Inhibitor
    Tetrahedron: Asymmetry, 2004
    Co-Authors: Nobuyuki Matsunaga, Tomohiro Kaku, Akio Ojida, Akihiro Tasaka
    Abstract:

    Abstract An asymmetric synthesis of the selective C 17,20 -Lyase Inhibitor 2 has been established in eight steps from 2,3-dihydroxynaphthalene 9 . The key steps are the enantioselective oxidation of ketone 17 to the chiral α-hydroxy ketone 18 and the diastereoselective Grignard reaction of 18 to the (2 R ,3 S )-diol 21 . In addition, a simple procedure for the preparation of imidazolyl 1,4-dimagnesium bromide has been established; the Grignard reaction of 11 using this reagent in the presence of cinchonine provided 2 with 44% ee.

Angela Brodie - One of the best experts on this subject based on the ideXlab platform.

  • 17α-Hydroxylase/17,20 Lyase Inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
    Molecular cancer therapeutics, 2008
    Co-Authors: Robert D. Bruno, Tony D. Gover, Angelika M. Burger, Angela Brodie, Vincent C. O. Njar
    Abstract:

    Inhibitors of the enzyme 17α-hydroxylase/17,20 Lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17α-hydroxylase/17,20 Lyase Inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 μmol/L and 7.55 μmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 μmol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 μmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]

  • 17α hydroxylase 17 20 Lyase Inhibitor vn 124 1 inhibits growth of androgen independent prostate cancer cells via induction of the endoplasmic reticulum stress response
    Molecular Cancer Therapeutics, 2008
    Co-Authors: Robert D. Bruno, Tony D. Gover, Angelika M. Burger, Angela Brodie, Vincent C. O. Njar
    Abstract:

    Inhibitors of the enzyme 17α-hydroxylase/17,20 Lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17α-hydroxylase/17,20 Lyase Inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 μmol/L and 7.55 μmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 μmol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 μmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]

  • Androgen receptor inactivation contributes to antitumor efficacy of 17A-hydroxylase/17,20-Lyase Inhibitor
    2008
    Co-Authors: Tadas S. Vasaitis, Vincent C. O. Njar, Aashvini Belosay, Adam Schayowitz, Aakanksha Khandelwal, Pankaj Chopra, Lalji K. Gediya, Zhiyong Guo, Hong-bin Fang, Angela Brodie
    Abstract:

    We previously reported that our novel compound 3Bhydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17A-hydroxylase/17,20-Lyase (CYP17) Inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 Inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm 3 in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/ 124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2348–57]

  • androgen receptor inactivation contributes to antitumor efficacy of 17a hydroxylase 17 20 Lyase Inhibitor
    2008
    Co-Authors: Tadas S. Vasaitis, Vincent C. O. Njar, Aashvini Belosay, Adam Schayowitz, Aakanksha Khandelwal, Pankaj Chopra, Lalji K. Gediya, Zhiyong Guo, Hong-bin Fang, Angela Brodie
    Abstract:

    We previously reported that our novel compound 3Bhydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17A-hydroxylase/17,20-Lyase (CYP17) Inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 Inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm 3 in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/ 124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2348–57]

  • 4 pregnene 3 one 20β carboxaldehyde a potent Inhibitor of 17α hydroxylase c17 20 Lyase and of 5α reductase
    The Journal of Steroid Biochemistry and Molecular Biology, 1992
    Co-Authors: Chong Son, P K Banks, Angela Brodie
    Abstract:

    Abstract The pregnene derivative, 4-pregnene-3-one-20β-carboxaldehyde (22-A) was evaluated as an Inhibitor of 17α-hydroxylase/C 17,20 -Lyase in rat testicular microsomes and of 5α-reductase in human prostatic homogenates. The effect of the compound in vivo was studied in adult male rats. The 22-A demonstrated potent and competitive inhibition of 17α-hydroxylase and C 17,20 -Lyase with K i values 8.48 and 0.41 μM, respectively, significantly below the K m values for these two enzymes (33.75 and 4.55 μM). This compound also showed potent inhibition of 5α-reductase with a K i value of 15.6 nM ( K m for this enzyme is 50 nM). By comparison, ketoconazole, a currently studied 17α-hydroxylase/C 17,20 -Lyase Inhibitor for the treatment of prostatic cancer, showed less potent inhibition of 17α-hydroxylase ( K i 39.5 μM) and C 17,20 -Lyase ( K i 3.6 μ M) and did not inhibit 5α-reductase. Progesterone which has been reported to inhibit the 17α-hydroxylase/C 17,20 -Lyase, did not significantly reduce the production of testosterone by rat testes in vitro in comparison to controls, while the same concentration of 22-A demonstrated a 42% reduction of testosterone biosynthesis. When the adult male rats were injected s.c. with 22-A at 50 mg/day/kg for a 2 week period, the testosterone concentrations in the rat sera were significantly lower than control values ( P 17,20 -Lyase, but is more potent for the C 17,20 -Lyase. The compound also inhibits 5α-reductase, and therefore may reduce biosynthesis of testosterone and dihydrotestosterone effectively. Thus, 22-A may be useful in the treatment of problems associated with the androgen excess and prostatic cancer.

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