Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia.
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ABSTRACT:
SUBMITTER: Terakado M
PROVIDER: S-EPMC5733272 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
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Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia.
Terakado Masahiko M Suzuki Hidehiro H Hashimura Kazuya K Tanaka Motoyuki M Ueda Hideyuki H Hirai Keisuke K Asada Masaki M Ikura Masahiro M Matsunaga Naoki N Saga Hiroshi H Shinozaki Koji K Karakawa Naoko N Takada Yuka Y Minami Masashi M Egashira Hiromu H Sugiura Yoshihiro Y Yamada Masanori M Nakade Shinji S Takaoka Yoshikazu Y
ACS medicinal chemistry letters 20171120 12
Scaffold hopping from the amide group of lead compound <b>ONO-7300243</b> (<b>1</b>) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA<sub>1</sub>) antagonist <b>4</b>. Wash-out experiments using rat isolated urethra showed that compound <b>4</b> possesses a tight binding feature to the LPA<sub>1</sub> receptor. Further modification of two phenyl groups of <b>1</b> to pyrrole and an indane moiety afforded an optimized compound <b>ONO-0300302</b> (<b ...[more]
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| S-EPMC3574942 | biostudies-literature
Project description:Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH.Levels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter.Human BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls.Oxidative stress and oxidative DNA damage are important in the pathogenesis of BPH.
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Project description:BackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.
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Project description:Benign prostatic hyperplasia (BPH) is prostate weighting f over 500g and is usually public in men older than fifty years. A case of 78-year-old man was referred to Sina hospital complaining of urinary frequency. His total prostate-specific antigen was 17.3 ng/mL and the volume of his prostate was measured at 350 mL by transrectal ultrasound. Simple prostatectomy was done and a huge adenoma was enucleated in an open retropubic manner weighting 1070g. "Giant BPH" is a rare pathology of the prostate gland. In this study, we report a successful enucleation of a giant BPH (1070 g) without any significant complications.
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Project description: Not available
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Project description:BPH samples harbored minimal copy number alterations, and the fraction of altered genome was far lower than primary prostate cancer and other neoplastic diseases.
2020-03-18 | GSE124187 | GEO
Project description:Transurethral resection of the prostate (TURP) became the gold standard surgical treatment for benign prostatic obstruction without undergoing randomized controlled trials against the predecessor standard in open suprapubic prostatectomy. TURP has historically been associated with significant morbidity and this has fuelled the development of minimally invasive surgical treatment options. Improvements in perioperative morbidity for TURP has been creating an ever increasing standard that must be met by any new technologies that are to be compared to this gold standard. Over recent years, there has been the emergence of novel minimally invasive treatments such as the prostatic urethral lift (PUL; UroLift System), convective WAter Vapor Energy (WAVE; Rezum System), Aquablation (AQUABEAM System), Histotripsy (Vortx Rx System) and temporary implantable nitinol device (TIND). Intraprostatic injections (NX-1207, PRX-302, botulinum toxin A, ethanol) have mostly been used with limited efficacy, but may be suitable for selected patients. This review evaluates these novel minimally invasive surgical options with special reference to the literature published in the past 5 years.
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Project description:PurposeBenign prostatic hyperplasia affects more than 50% of men by age 60 years, and is the cause of millions of dollars in health care expenditure for the treatment of lower urinary tract symptoms and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic benign prostatic hyperplasia. At least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5α-reductase type 2, and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of benign prostatic hyperplasia progression as well as the key genes and signaling pathways implicated in the process such as 5α-reductase. We also explore the potential of biomarker screening and gene specific therapies as tools to risk stratify patients with benign prostatic hyperplasia and identify those with symptomatic or medically resistant forms.Materials and methodsA PubMed® literature search of current and past peer reviewed literature on prostate development, lower urinary tract symptoms, benign prostatic hyperplasia pathogenesis, targeted therapy, biomarkers, epigenetics, 5α-reductase type 2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined, as were their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications.ResultsBenign prostatic hyperplasia is associated with a state of hyperplasia of the stromal and epithelial compartments, with 5α-reductase type 2 and androgen signaling having key roles in the development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities have complex roles in prostate tissue homeostasis as well as its evolution into the clinical state of benign prostatic hyperplasia. Resistance to medical therapy with finasteride may occur through silencing of the 5α-reductase type 2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5α-reductase type 2. Novel biomarkers such as single nucleotide polymorphisms may be used to risk stratify patients with symptomatic benign prostatic hyperplasia and identify those at risk for progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate benign prostatic hyperplasia progression and may offer alternative targets for medical therapy.ConclusionsProgressive worsening of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia is the result of multiple pathways including androgen receptor signaling, proinflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene specific targets. As personalized medicine continues to develop, the ability to risk stratify patients with symptomatic benign prostatic hyperplasia, identify those at higher risk for progression, and seek alternative therapies for those in whom conventional options are likely to fail will become the standard of targeted therapy.
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