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Urszula L McClurg, Mahsa Azizyan, Daniel T Dransfield, Nivedita Namdev, Nay C T H Chit, Sirintra Nakjang, Craig N Robson
Metastatic castration resistant prostate cancer is one of the main causes of male cancer associated deaths worldwide. Development of resistance is inevitable in patients treated with anti-androgen therapies. This highlights a need for novel therapeutic strategies that would be aimed upstream of the androgen receptor (AR). Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway...
May 18, 2018: Oncotarget
Rami Masamrekh, Alexey Kuzikov, Alexander Veselovsky, Iliya Toropygin, Tatsiana Shkel, Natalia Strushkevich, Andrei Gilep, Sergey Usanov, Alexander Archakov, Victoria Shumyantseva
Abiraterone and galeterone induce type I differential spectral changes in human sterol 14α-demethylase (cytochrome P450 51A1, CYP51A1) with the sigmoidal shape of the binding curve. After approximation of the data by Hill model, the half-saturation concentrations (K0.5 ) were estimated as 22 ± 1 μM and 16 ± 1 μM and the Hill coefficients as 2.4 ± 0.2 and 1.97 ± 0.23 for abiraterone and galeterone, respectively. We analyzed the catalytic activity of CYP51A1 towards abiraterone and galeterone using an electrochemical system based on recombinant CYP51A1 immobilized on the screen-printed graphite electrode (SPE) modified by didodecyldimethylammonium bromide (DDAB) film...
May 21, 2018: Journal of Inorganic Biochemistry
Caleb Keng Yan Yip, Sumit Bansal, Siew Ying Wong, Aik Jiang Lau
Galeterone and abiraterone acetate are antiandrogens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1) and compared their effects to those of other antiandrogens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 μ M) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols...
April 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Vladimir A Zolottsev, Yaroslav V Tkachev, Alexandra S Latysheva, Vladimir A Kostin, Roman A Novikov, Vladimir P Timofeev, Galina E Morozevich, Alexey V Kuzikov, Victoria V Shumyantseva, Alexander Y Misharin
Four new 4,5-dihydro-1,3-oxazole, and four new benzo-[d]-oxazole derivatives of [17(20)E]-21-norpregnene, differing in the structure of steroid moiety, were synthesized and evaluated for their potency to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity. Among new compounds, the only oxazolinyl derivative comprising 5-oxo-4,5-seco-3-yn- moiety potently inhibited CYP17A1. Binding modes of the oxazolinyl derivatives of [17(20)E]-21-norpregnene were analyzed by molecular dynamics simulations, and model of alternate, water-bridged type II interaction was proposed for these compounds...
January 2018: Steroids
David J McCarty, Weiliang Huang, Maureen A Kane, Puranik Purushottamachar, Lalji K Gediya, Vincent C O Njar
The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility. Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide...
October 24, 2017: Oncotarget
Laura L Romero-Hernández, Penélope Merino-Montiel, Socorro Meza-Reyes, José Luis Vega-Baez, Óscar López, José M Padrón, Sara Montiel-Smith
Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields...
January 1, 2018: European Journal of Medicinal Chemistry
Andrew K Kwegyir-Afful, Francis N Murigi, Puranik Purushottamachar, Vidya P Ramamurthy, Marlena S Martin, Vincent C O Njar
Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC...
August 8, 2017: Oncotarget
Mohammad Alyamani, Zhenfei Li, Michael Berk, Jianneng Li, Jingjie Tang, Sunil Upadhyay, Richard J Auchus, Nima Sharifi
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ(5),3β-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ(4)-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3β-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5β-reduced metabolites...
July 20, 2017: Cell Chemical Biology
Elyse M Petrunak, Steven A Rogers, Jeffrey Aubé, Emily E Scott
Human steroidogenic cytochrome P450 17A1 (CYP17A1) is a bifunctional enzyme that performs both hydroxylation and lyase reactions, with the latter required to generate androgens that fuel prostate cancer proliferation. The steroid abiraterone, the active form of the only CYP17A1 inhibitor approved by the Food and Drug Administration, binds the catalytic heme iron, nonselectively impeding both reactions and ultimately causing undesirable corticosteroid imbalance. Some nonsteroidal inhibitors reportedly inhibit the lyase reaction more than the preceding hydroxylase reaction, which would be clinically advantageous, but the mechanism is not understood...
June 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Andrew K Kwegyir-Afful, Francis N Murigi, Puranik Purushottamachar, Vidya P Ramamurthy, Marlena S Martin, Vincent C O Njar
Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC...
December 24, 2016: Oncotarget
Rana R McKay, Lillian Werner, Matthew Fiorillo, Jennifer Roberts, Elisabeth I Heath, Glenn J Bubley, Robert Bruce Montgomery, Mary-Ellen Taplin
BACKGROUND: Galeterone is a multi-targeted agent with activity as a CYP17 inhibitor, androgen receptor antagonist, and also causes androgen receptor degradation. It has shown meaningful anti-tumor activity with a well-tolerated safety profile in patients with castration-resistant prostate cancer (CRPC) in phase I and II studies; however, the efficacy of currently approved CRPC therapies after treatment with galeterone is unknown. In this study, we evaluate prostate specific antigen (PSA) response of non-protocol therapies following galeterone in a subset of patients treated on the Androgen Receptor Modulation Optimized for Response (ARMOR) 2 study...
October 27, 2016: Clinical Genitourinary Cancer
Andrew K Kwegyir-Afful, Robert D Bruno, Puranik Purushottamachar, Francis N Murigi, Vincent C O Njar
Metastatic castration-resistant prostate cancer (mCRPC) accounts for a high percentage of prostate cancer mortality. The proprietary compound galeterone (gal) was designed to inhibit proliferation of androgen/androgen receptor (AR)-dependent prostate cancer cell in vitro and in vivo and is currently in phase III clinical development. Additionally, clinical studies with gal revealed its superb efficacy in four different cohorts of patients with mCRPC, including those expressing splice variant AR-V7. Preclinical studies with gal show that it also exhibits strong antiproliferative activities against AR-negative prostate cancer cells and tumors through a mechanism involving phosphorylation of eIF2α, which forms an integral component of the eukaryotic mRNA translation complex...
November 2016: FEBS Journal
Yusuke Imamura, Amy H Tien, Jinhe Pan, Jacky K Leung, Carmen A Banuelos, Kunzhong Jian, Jun Wang, Nasrin R Mawji, Javier Garcia Fernandez, Kuo-Shyan Lin, Raymond J Andersen, Marianne D Sadar
Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD-targeted (AR LBD-targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V-positive lesions to determine whether they will benefit from further AR LBD-targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone...
July 21, 2016: JCI Insight
Diogo A Bastos, Emmanuel S Antonarakis
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide...
2016: Drug Design, Development and Therapy
Puranik Purushottamachar, Andrew K Kwegyir-Afful, Marlena S Martin, Vidya P Ramamurthy, Senthilmurugan Ramalingam, Vincent C O Njar
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...
July 14, 2016: ACS Medicinal Chemistry Letters
Brandon M Bordeau, Daniel A Ciulla, Brian P Callahan
Abiraterone, a potent inhibitor of the human enzyme CYP17A1 (cytochrome P450c17), provides a last line of defense against ectopic androgenesis in advanced prostate cancer. Herein we report an unprecedented off-target interaction between abiraterone and oncogenic hedgehog proteins. Our experiments indicate that abiraterone and its structural congener, galeterone, can replace cholesterol as a substrate in a specialized biosynthetic event of hedgehog proteins, known as cholesterolysis. The off-target reaction generates covalent hedgehog-drug conjugates...
September 20, 2016: ChemMedChem
Sameer S Udhane, Bernhard Dick, Qingzhong Hu, Rolf W Hartmann, Amit V Pandey
The orteronel, abiraterone and galeterone, which were developed to treat castration resistant prostate cancer, inhibit 17,20 lyase activity but little is known about their effects on adrenal androgen biosynthesis. We studied the effect of several inhibitors and found that orteronel was selective towards 17,20 lyase activity than abiraterone and galeterone. Gene expression analysis showed that galeterone altered the expression of HSD3B2 but orteronel did not change the expression of HSD3B2, CYP17A1 and AKR1C3...
September 2, 2016: Biochemical and Biophysical Research Communications
Jacqueline Bogner, Kourosh Zolghadr, Ian Hickson, Tina Romer, Larisa Yurlova
The androgen receptor (AR) is an important target for drug therapies combating prostate cancer. However, various acquired mutations within the AR sequence often render this receptor resistant to treatment. Ligand-induced interaction between the N- and C-termini of the AR marks the initial step in the AR signaling cascade and can thus serve as an early read-out for analysis of potential antagonists of wt and mutant AR. To measure changes of the N/C interaction in the wt and mutant AR variants upon the addition of inhibitors, we applied our recently developed Fluorescent Two-Hybrid (F2H) assay...
February 2017: Journal of Steroid Biochemistry and Molecular Biology
Athanasios Dellis, Athanasios G Papatsoris
INTRODUCTION: Prostate cancer is the most common cancer in elderly males. Regardless of the initial hormonal treatment in metastatic disease, a significant proportion of patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of oral medications such as abiraterone acetate and enzalutamide. Relevant research is accelerated with numerous agents being tested for the management of CRPC...
June 2016: Expert Opinion on Investigational Drugs
Benjamin L Maughan, Emmanuel S Antonarakis
Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients...
December 2015: Current Treatment Options in Oncology
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