Evolution of Peptide-Based Prostate-Specific Membrane Antigen (PSMA) Inhibitors: An Approach to Novel Prostate Cancer Therapeutics

2020 ◽  
Vol 27 ◽  
Author(s):  
Andrew Siow ◽  
Renata Kowalczyk ◽  
Margaret A. Brimble ◽  
Paul W.R. Harris
Keyword(s):  
Prostate Cancer ◽  
Clinical Application ◽  
Rational Design ◽  
Therapeutic Potential ◽  
Rapid Development ◽  
Cancer Therapeutics ◽  
Prostate Specific Membrane Antigen ◽  
Specific Membrane

Background: Prostate cancer is one of the most common cancers worldwide, with approximately 1.1 million cases diagnosed annually. The rapid development of molecular imaging has facilitated greater structural understanding which can help formulate novel combination therapeutic regimens and more accurate diagnosis avoiding unnecessary prostate biopsies. This accumulated knowledge also provides greater understanding into aggressive stages of the disease and tumour recurrence. Recently, much progress has been made on developing peptidomimetic-based inhibitors as promising candidates to effectively bind to the prostate-specific membrane antigen (PSMA) which is expressed by prostate cancer cells. Objective: In this review, recent advances covering small-molecule and peptide-based PSMA inhibitors will be extensively reviewed providing a base for the rational design of future PSMA inhibitors. Method: Herein, we review the literature on selected PSMA inhibitors that have been developed from 1996-2020, emphasizing recent synthetic advances and chemical strategies whilst highlighting therapeutic potential and drawbacks of each inhibitor. Results: Synthesized inhibitors presented in this review demonstrate the clinical application of certain PSMA inhibitors exhibited in vitro and in vivo. Conclusion: This review highlights the clinical potential of PSMA inhibitors, analyzing the advantages and setbacks of the chemical synthetic methodologies utilized, setting precedence for the discovery of novel PSMA inhibitors for future clinical application.

scholarly journals Dual PI3 K/mTOR inhibition reduces prostate cancer bone engraftment altering tumor-induced bone remodeling

Tumor Biology ◽  
2018 ◽  
Vol 40 (4) ◽  
pp. 101042831877177 ◽  
Author(s):  
Andrea Mancini ◽  
Alessandro Colapietro ◽  
Simona Pompili ◽  
Andrea Del Fattore ◽  
Simona Delle Monache ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Therapeutic Potential ◽  
Disease Free Survival ◽  
Bone Lesions ◽  
Metastatic Progression ◽  
Mtor Inhibition ◽  
Osteoblast Activity

Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions.

scholarly journals PSMA-Targeting Redox Hyperbranched Poly (Amido Amine)-Mediated miR-133a-3p Delivery to Inhibit Bone Metastasis of Prostate Cancer

2020 ◽  
Author(s):  
Yongheng Ye ◽  
Lingli Zhang ◽  
Yuhu Dai ◽  
Zhi Wang ◽  
Cuie Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Therapeutic Potential ◽  
Tumor Model ◽  
Lncap Cells ◽  
Systemic Delivery ◽  
Formidable Challenge ◽  
Hyperbranched Poly

Abstract Treatment of bone metastasis of prostate cancer remains a formidable challenge. The skeleton has a poorer blood supply, leading to inadequate drug distribution into the bone after administration. This study aimed to develop aptamer-anchored hyperbranched poly (amido amine) (HPAA) for the systemic delivery of miRNA-133a-3p and to evaluate its therapeutic potential against bone metastasis of prostate cancer in vivo and in vitro. A glutathione (GSH)-responsive cationic HPAA was prepared by the Michael addition reaction. Furthermore, HPAA-PEG was produced by PEGylation, and then the aptamer targeted to prostate-specific membrane antigen (PSMA) was conjugated to the HPAA-PEG. The obtained HPAA-PEG-APT could form nanocomplexes with miRNA-133a-3p through electrostatic adsorption. The results of immunocytochemistry indicated that the complexes could target PSMA-expressing LNCaP cells. The ability of HPAA-PEG-APT to facilitate the delivery of miRNA-133a-3p into LNCaP cells was proven, and HPAA-PEG-APT/miRNA-133a-3p demonstrated enhanced antitumor activity, lower cytotoxicity and better biocompatibility in vitro. Moreover, in a mouse tibial injection tumor model, the intravenous injection of the HPAA-PEG-APT/miRNA-133a-3p complex significantly inhibited cancer growth and extended the survival time. In summary, this study provided an aptamer-anchored HPAA-loaded gene system to deliver miRNA-133a-3p for better therapeutic efficacy of bone metastasis of prostate cancer.

scholarly journals A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase

Pharmacology ◽  
2018 ◽  
Vol 102 (5-6) ◽  
pp. 233-243 ◽  
Author(s):  
Sarah F. Giardina ◽  
Douglas S. Werner ◽  
Maneesh Pingle ◽  
Donald E. Bergstrom ◽  
Lee D. Arnold ◽  
...  
Keyword(s):  
Active Sites ◽  
Rational Design ◽  
Therapeutic Potential ◽  
X Ray Crystallography ◽  
Inflammatory Stimuli ◽  
Invaluable Tool ◽  
Xenograft Models ◽  
Orally Bioavailable

β-Tryptase is released from mast cells upon degranulation in response to allergic and inflammatory stimuli. Human tryptase is a homotetrameric serine protease with 4 identical active sites directed toward a central pore. These active sites present an optimized scenario for the rational design of bivalent inhibitors, which bridge 2 adjacent active sites. Using (3-[1-acylpiperidin-4-yl]phenyl)methanamine as the pharmacophoric core and a disiloxane linker to span 2 active sites we have successfully produced a novel bivalent tryptase inhibitor, compound 1a, with a comparable profile to previously described inhibitors. Pharmacological properties of compound 1a were studied in a range of in vitro enzymic and cellular screening assays, and in vivo xenograft models. This non-peptide inhibitor of tryptase demonstrated superior activity (IC50 at 100 pmol/L tryptase = 1.82 nmol/L) compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and 1a demonstrated good oral bioavailability and efficacy in HMC-1 xenograft models. Furthermore, compound 1a demonstrated extremely slow off rates and high selectivity against-related proteases. This highly potent, orally bioavailable and selective inhibitor of human tryptase will be an invaluable tool in future studies to explore the therapeutic potential of attenuating the activity of this elusive target.

Prostate specific membrane antigen (PSMA) is a tissue-specific target for adenoviral transduction of prostate cancer in vitro

The Prostate ◽  
2004 ◽  
Vol 62 (3) ◽  
pp. 253-259 ◽  
Author(s):  
R. Kraaij ◽  
A.L.C.T. van Rijswijk ◽  
M.H.A. Oomen ◽  
H.J. Haisma ◽  
C.H. Bangma
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Membrane Antigen ◽  
Tissue Specific ◽  
Specific Target ◽  
Adenoviral Transduction ◽  
Specific Membrane

scholarly journals Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

2021 ◽  
Author(s):  
Asmaa El-Kenawi ◽  
William Dominguez-Viqueira ◽  
Min Liu ◽  
Shivanshu Awasthi ◽  
Aysenur Keske ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Nuclear Translocation ◽  
Cholesterol Metabolism ◽  
Therapeutic Potential ◽  
Cholesterol Homeostasis ◽  
Castration Resistant Prostate Cancer ◽  
Macrophage Depletion

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

scholarly journals Development of an Albumin-Based PSMA Probe With Prolonged Half-Life

2020 ◽  
Vol 7 ◽  
Author(s):  
Teli Liu ◽  
Chen Liu ◽  
Yanan Ren ◽  
Xiaoyi Guo ◽  
Jinquan Jiang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Half Life ◽  
Radiochemical Purity ◽  
Specific Activity ◽  
Tumor Burden ◽  
Tumor Bearing ◽  
Specific Membrane ◽  
Psma Inhibitor

Prostate-specific membrane antigen (PSMA) is an attractive target for the diagnosis and therapy of prostate cancer as it is specifically overexpressed in prostate cancer cells. Improving the circulation of radioligands in the blood is considered as an effective strategy that can improve tumor burden, which benefits detection of small lesions and improves the effect of PSMA radioligand therapy (PRLT). In this study, we introduced maleimidopropionic acid (MPA) to a PSMA-targeted tracer and developed Al18F-PSMA-CM, which targets human serum albumin (HSA) binding and PSMA. Al18F-PSMA-CM is evaluated in vitro and in vivo for stability, PSMA specificity, and biodistribution in 22Rv1 tumor-bearing mice. Al18F-PSMA-CM was prepared with a radiochemical purity of >99% and specific activity of 11.22–18.70 MBq/nmol. Al18F-PSMA-CM was stable in vitro and in vivo and prolonged circulation in blood with a binding ratio of 47 ± 3.2% and Kd value of 3.08 ± 0.45 nM to HSA. The uptake of Al18F-PSMA-CM in PSMA(+) 22Rv1 cells was increased in 2 h, and the uptake was blocked by a PSMA inhibitor, ZJ-43. The Kd value of Al18F-PSMA-CM to PSMA was 8.46 ± 0.24 nM. Al18F-PSMA-CM was accumulated in kidneys and 22Rv1 tumors [74.76 ± 15.42 and 6.16 ± 0.74 ID%/g at 2 h post injection (p.i.)], which were decreased by −80.0 and −84.3% when co-injected with ZJ-43. Al18F-PSMA-CM showed high PSMA specificity and accumulated in 22Rv1 tumors with increasing uptake in 4 h. MPA moiety showed the ability to prolong the half-life of tracers, and the MPA-conjugated tracer showed the potential to improve tumor uptake. MPA may be a choice to develop radiopharmaceuticals for PRLT of prostate cancer.

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