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Valeri Vasioukhin - One of the best experts on this subject based on the ideXlab platform.
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Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis
2016Co-Authors: Xi Tang, Sumit S. Mahajan, Liem T. Nguyen, François Béliveau, Richard Leduc, Julian A. Simon, Valeri VasioukhinAbstract:This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The development of effective therapies inhibiting prostate cancer progression and metastasis may substantially impact prostate cancer mortality and potentially reduce the rates of invasive treatments by enhancing the safety of active surveillance strategies. Hepsin (HPN) is a cell surface serine protease amplified in a subset of human sarcomas (7.2%), as well as in ovarian (10%), lung adeno (5.4%), lung squamous cell (4.5%), adenoid cystic (5%), breast (2.6%), uterine (1.7%) and colon (1.4%) carcinomas. While HPN is not amplified in prostate cancer, it is one of the most prominently overexpressed genes in the majority of human prostate tumors and genetic experiments in mice indicate that Hepsin promotes prostate cancer metastasis, particularly metastasis to the bone marrow. We report here the development, analysis and animal trial of the small-molecule Hepsin inhibitor HepIn-13. Long-term exposure to HepIn-13 inhibited bone, liver and lung metastasis in a murine model of metastatic prostate cancer. These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis
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Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis.
Oncotarget, 2014Co-Authors: Xi Tang, Sumit S. Mahajan, Liem T. Nguyen, François Béliveau, Richard Leduc, Julian A. Simon, Valeri VasioukhinAbstract:The development of effective therapies inhibiting prostate cancer progression and metastasis may substantially impact prostate cancer mortality and potentially reduce the rates of invasive treatments by enhancing the safety of active surveillance strategies. Hepsin (HPN) is a cell surface serine protease amplified in a subset of human sarcomas (7.2%), as well as in ovarian (10%), lung adeno (5.4%), lung squamous cell (4.5%), adenoid cystic (5%), breast (2.6%), uterine (1.7%) and colon (1.4%) carcinomas. While HPN is not amplified in prostate cancer, it is one of the most prominently overexpressed genes in the majority of human prostate tumors and genetic experiments in mice indicate that Hepsin promotes prostate cancer metastasis, particularly metastasis to the bone marrow. We report here the development, analysis and animal trial of the small-molecule Hepsin inhibitor HepIn-13. Long-term exposure to HepIn-13 inhibited bone, liver and lung metastasis in a murine model of metastatic prostate cancer. These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.
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Abstract 535: Development of small-molecule Hepsin inhibitors
Tumor Biology, 2010Co-Authors: Xi Tang, Valeri VasioukhinAbstract:Hepsin is a cell-surface serine protease prominently overexpressed in the majority of human prostate tumors. We and others have previously demonstrated that Hepsin promotes prostate cancer progression and metastasis in vivo. These findings identified Hepsin as a very attractive therapeutic target in prostate cancer. To develop small molecule Hepsin inhibitors, we have previously performed in vitro screenings of libraries of small drug-like molecules. These efforts resulted in identification of several lead compounds inhibiting Hepsin proteolytic activity. We now identified and performed additional characterization of the derivatives of most potent Hepsin lead inhibitors. We also developed a novel cell-based Hepsin activity assay, which utilizes expressed on the cell-surface human Hepsin and C-terminally HA-tagged pro-HGF, as its specific cleavage substrate. Overall, this study identified specific and potent small-molecule Hepsin inhibitors that may be potentially used in the future as therapeutic agents to attenuate prostate cancer progression in the ‘watchful waiting’ cohort of prostate cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 535.
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Hepsin cooperates with MYC in the progression of adenocarcinoma in a prostate cancer mouse model
The Prostate, 2009Co-Authors: Srinivas Nandana, Katharine Ellwood-yen, Charles L. Sawyers, Marcia L. Wills, Brandy Weidow, Thomas C. Case, Valeri Vasioukhin, Robert J MatusikAbstract:BACKGROUND Hepsin is a cell surface protease that is over-expressed in more than 90% of human prostate cancer cases. The previously developed Probasin-Hepsin/Large Probasin-T antigen (PB-Hepsin/LPB-Tag) bigenic mouse model of prostate cancer demonstrates that Hepsin promotes primary tumors that are a mixture of adenocarcinoma and neuroendocrine (NE) lesions, and metastases that are NE in nature. However, since the majority of human prostate tumors are adenocarcinomas, the contribution of Hepsin in the progression of adenocarcinoma requires further investigation. METHODS We crossed the PB-Hepsin mice with PB-Hi-myc transgenic mouse model of prostate adenocarcinoma and characterized the tumor progression in the resulting PB-Hepsin/PB-Hi-myc bigenic mice. RESULTS We report that PB-Hepsin/PB-Hi-myc bigenic mice develop invasive adenocarcinoma at 4.5 months. Further, histological analysis of the 12- to 17-month-old mice revealed that the PB-Hepsin/PB-Hi-myc model develops a higher grade adenocarcinoma compared with age-matched tumors expressing only PB-Hi-myc. Consistent with targeting Hepsin to the prostate, the PB-Hepsin/PB-Hi-myc tumors showed higher Hepsin expression as compared to the age-matched myc tumors. Furthermore, endogenous expression of Hepsin increased in the PB-Hi-myc mice as the tumors progressed. CONCLUSIONS Although we did not detect any metastases from the prostates in either the PB-Hepsin/PB-Hi-myc or the PB-Hi-myc mice, our data suggests that Hepsin and myc cooperate during the progression to high-grade prostatic adenocarcinoma. Prostate 70: 591–600, 2010. © 2009 Wiley-Liss, Inc.
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Identification and characterization of small-molecule inhibitors of Hepsin.
Molecular cancer therapeutics, 2008Co-Authors: John R. Chevillet, Julian A. Simon, Gemma J. Park, Antonio Bedalov, Valeri VasioukhinAbstract:Hepsin is a type II transmembrane serine protease overexpressed in the majority of human prostate cancers. We recently demonstrated that Hepsin promotes prostate cancer progression and metastasis and thus represents a potential therapeutic target. Here we report the identification of novel small-molecule inhibitors of Hepsin catalytic activity. We utilized purified human Hepsin for high-throughput screening of established drug and chemical diversity libraries and identified sixteen inhibitory compounds with IC(50) values against Hepsin ranging from 0.23-2.31 microM and relative selectivity of up to 86-fold or greater. Two compounds are orally administered drugs established for human use. Four compounds attenuated Hepsin-dependent pericellular serine protease activity in a dose dependent manner with limited or no cytotoxicity to a range of cell types. These compounds may be used as leads to develop even more potent and specific inhibitors of Hepsin to prevent prostate cancer progression and metastasis.
Shijin Sun - One of the best experts on this subject based on the ideXlab platform.
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Hepsin: a multifunctional transmembrane serine protease in pathobiology.
The FEBS journal, 2020Co-Authors: Lina Wang, Shijin SunAbstract:Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that Hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, Hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, Hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated Hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for Hepsin activity. In this review, we discuss the current knowledge regarding Hepsin biosynthesis, activation, and functions in pathobiology.
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N-glycan in the scavenger receptor cysteine-rich domain of Hepsin promotes intracellular trafficking and cell surface expression.
International journal of biological macromolecules, 2020Co-Authors: Shijin Sun, Lina Wang, Shengnan Zhang, Ce Zhang, Yue Chen, Ningzheng DongAbstract:The group A scavenger receptor cysteine-rich (SRCR) domain is a conserved module present in numerous proteins involved in diverse biological processes. Hepsin, a hepatic protease implicated in many cancers, consists of a cytoplasmic tail, a transmembrane domain and an extracellular regions with a group A SRCR domain and a serine protease domain. Like in many SRCR-containing proteins, the SRCR domain in Hepsin has an N-glycosylation site, but its functional significance is unknown. In this study, we confirmed N-glycosylation at Asn112 in Hepsin by glycosidase digestion and site-directed mutagenesis in human hepatoma cells. In Western blotting, fluorogenic substrate assay, flow cytometry, and protein-chase experiments, we found that Asn112 to Gln (N112Q) mutation inhibited Hepsin intracellular trafficking, cell surface expression, and zymogen activation. By immunofluorescent staining, we found that the N112Q mutant was more abundant than wild-type Hepsin in the endoplasmic reticulum (ER). Further co-immunoprecipitation studies indicated increased binding of the N112Q mutant to calnexin and binding-immunoglobulin protein (BiP), two ER chaperones. Our results indicate that the N-glycan in the SRCR domain of Hepsin promotes intracellular trafficking and cell surface expression, possibly by a calnexin-dependent mechanism in facilitating ER exiting.
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autoactivation and calpain 1 mediated shedding of Hepsin in human hepatoma cells
Biochemical Journal, 2019Co-Authors: Lina Wang, Shijin Sun, Ce Zhang, Yue Chen, Hao Wang, Meng Liu, Ningzheng DongAbstract:Hepsin is a transmembrane serine protease implicated in many biological processes, including hepatocyte growth, urinary protein secretion, auditory nerve development, and cancer metastasis. Zymogen activation is critical for Hepsin function. To date, how Hepsin is activated and regulated in cells remains an enigma. In this study, we conducted site-directed mutagenesis, cell expression, plasma membrane protein labeling, trypsin digestion, Western blotting, and flow cytometry experiments in human hepatoma HepG2 cells, where Hepsin was originally discovered, and SMMC-7721 cells. Our results show that Hepsin is activated by autocatalysis on the cell surface but not intracellularly. Moreover, we show that Hepsin undergoes ectodomain shedding. In the conditioned medium from HepG2 and SMMC-7721 cells, we detected a soluble fragment comprising nearly the entire extracellular region of Hepsin. By testing protease inhibitors, gene knockdown, and site-directed mutagenesis, we identified calpain-1 as a primary protease that acted extracellularly to cleave Tyr52 in the juxtamembrane space of Hepsin. These results provide new insights into the biochemical and cellular mechanisms that regulate Hepsin expression and activity.
Daniel Kirchhofer - One of the best experts on this subject based on the ideXlab platform.
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An allosteric anti-Hepsin antibody derived from a constrained phage display library
Protein Engineering Design and Selection, 2012Co-Authors: Rajkumar Ganesan, S. Jack Lin, Kyle E Landgraf, Paul Moran, Yingnan Zhang, Daniel KirchhoferAbstract:The serine protease Hepsin is highly upregulated in prostate cancer and is implicated in tumor progression. Therefore, specific inhibition of Hepsin enzymatic activity by an antibody constitutes an attractive therapeutic approach. Here, we report the identification of the anti-Hepsin antibody Fab25 by screening of a Fab phage display library with a restricted chemical diversity at the complementary determining regions. Hepsin with its S1 pocket occupied by 3,4-dichloro-isocoumarin was used as the 'bait' for library screening. Fab25 was highly specific and it potently inhibited Hepsin activity toward a panel of synthetic and macromolecular substrates. Biochemical and enzymatic studies with synthetic substrates of variable length suggested that Fab25 acts as an allosteric inhibitor based on non-competitive inhibition kinetics. Isothermal titration calorimetric experiments showed that the high-affinity (K(D) 6.1 nM) binding of Fab25 with Hepsin is enthalpically driven. Despite an unusually long CDR-H3 loop with several potential Hepsin cleavage sites (Lys, Arg residues), Fab25 was not processed by Hepsin. Antibody-25 should be valuable for investigating Hepsin's role in cancer progression and for potential therapeutic applications. Furthermore, the herein presented phage display strategy using an active site-modified protease should be widely applicable for identifying potential allosteric anti-protease antibodies.
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Proteolytic Activation of Pro-Macrophage-Stimulating Protein by Hepsin
Molecular cancer research : MCR, 2011Co-Authors: Rajkumar Ganesan, S. Jack Lin, Ganesh Kolumam, Ming-hong Xie, Lydia Santell, Robert A. Lazarus, Amitabha Chaudhuri, Daniel KirchhoferAbstract:Macrophage-stimulating protein (MSP) is a plasminogen-related growth factor and ligand for the receptor tyrosinekinase RON.TheMSP/RONsystem promoteswoundhealing andinvasivetumorgrowthand suppresses proinflammatory immune response. MSP binding to RON requires proteolytic conversion of the inactive singlechain form (pro-MSP) into the disulfide-linked a/b heterodimer. The pro-MSP cleavage sequence (Ser-Lys-LeuArg 483 #Val 484 ) closely matches the substrate recognition sequences of Hepsin, a type II transmembrane serine protease, that is overexpressed in several cancers. Here, we show that recombinant Hepsin cleaves pro-MSP at the consensus site Arg 483 -Val 484 with superior efficiency compared with the known activators MT-SP1 and hepatocyte growth factor activator (HGFA). At least 50% of pro-MSP was processed within 1 hour at a Hepsin concentration of2.4nmol/Land atamolar enzymetosubstrateratio of1:500.Anuncleavable single-chain variant of MSP weakly bound to a RON–Fc fusion protein, whereas Hepsin-cleaved MSP bound with a KD of 10.3 nmol/ L, suggesting that the high-affinity binding site in MSP b-chain was properly formed. LNCaP prostate cancer cells overexpressingHepsinonthecellsurfaceefficiently activatedpro-MSP,whichwasblockedbyaspecificanti-Hepsin antibody. Incubation ofpro-MSP withHepsin led torobustRON-mediated phosphorylation of mitogen-activated protein kinase, ribosomal S6 protein, and Akt in human A2780 ovarian carcinoma cells stably expressing RON protein. In macrophages, pro-MSP with Hepsin induced chemotaxis and attenuated lipopolysaccharide-dependent production of nitric oxide. These findings suggest that the MSP/RON signaling pathway may be regulated by Hepsin in tissue homeostasis and in disease pathologies, such as in cancer and immune disorders. Mol Cancer Res; 9(9); 1175–86. � 2011 AACR.
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laminin 332 is a substrate for Hepsin a protease associated with prostate cancer progression
Journal of Biological Chemistry, 2008Co-Authors: Manisha Tripathi, Rajkumar Ganesan, Daniel Kirchhofer, Srinivas Nandana, Hironobu Yamashita, Vito QuarantaAbstract:Abstract Hepsin, a cell surface protease, is widely reported to be overexpressed in more than 90% of human prostate tumors. Hepsin expression correlates with tumor progression, making it a significant marker and target for prostate cancer. Recently, it was reported that in a prostate cancer mouse model, Hepsin up-regulation in tumor tissue promotes progression and metastasis. The underlying mechanisms, however, remain largely uncharacterized. Hepsin transgenic mice displayed reduced laminin-332 (Ln-332) expression in prostate tumors. This is an intriguing cue, since proteolytic processing of extracellular matrix macromolecules, such as Ln-332, is believed to be involved in cancer progression, and Ln-332 expression is lost during human prostate cancer progression. In this study, we provide the first direct evidence that Hepsin cleaves Ln-332. Cleavage is specific, since it is both inhibited in a dose-dependent manner by a Hepsin inhibitor (Kunitz domain-1) and does not occur when catalytically inactive Hepsin is used. By Western blotting and mass spectrometry, we determined that Hepsin cleaves the β3 chain of Ln-332. N-terminal sequencing identified the cleavage site at β3 Arg245, in a sequence context (SQLR245↓LQGSCFC) conserved among species and in remarkable agreement with reported consensus target sequences for Hepsin activity. In vitro cell migration assays showed that Hepsin-cleaved Ln-332 enhanced motility of DU145 prostate cancer cells, which was inhibited by Kunitz domain-1. Further, Hepsin-overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Direct cleavage of Ln-332 may be one mechanism by which Hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility.
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Hepsin overexpression promotes tumor growth in an orthotopic prostate cancer model
Cancer Research, 2007Co-Authors: Buer Wang, Alvin Gogineni, Stuart Bunting, Weiqiang Gao, Mary J. Cole, Leo Deguzman, Daniel KirchhoferAbstract:AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3096 Hepsin, a type II transmembrane serine protease, is highly upregulated in prostate cancer. Hepsin promotes tumor metastasis in a mouse model of prostate cancer, suggesting a role in the later tumor stages. However, Hepsin protein levels are already high in pre-cancerous lesions and remain elevated in the carcinoma and metastasis stages. In this study, we investigated the role of Hepsin in primary tumor growth in an orthotopic prostate cancer model by use of Hepsin-transfected LnCaP cell lines, which also stably expressed luciferase for bioluminescence imaging. The LnCaP-34 cells stably expressed Hepsin protein on the cell surface at about 5-fold higher levels than the LnCaP-17 cells, which only expressed endogenous Hepsin. The higher Hepsin levels on LnCaP-34 correlated with increased Hepsin enzymatic activity towards pro-urokinase type plasminogen activator. 1x106 LnCaP-17 or LnCaP-34 cells were injected into the left anterior lobe of the prostate of SCID-beige mice (20 animals per group) and tumors were analyzed after 16 weeks. We found a higher tumor occurrence (80% vs 58%) and lower body weights (20.8±0.8g vs. 23.5±0.9g; p
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Hepsin overexpression promotes tumor growth in an orthotopic prostate cancer model
Cancer Research, 2007Co-Authors: Buer Wang, Alvin Gogineni, Stuart Bunting, Weiqiang Gao, Mary J. Cole, Leo Deguzman, Daniel KirchhoferAbstract:AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3096 Hepsin, a type II transmembrane serine protease, is highly upregulated in prostate cancer. Hepsin promotes tumor metastasis in a mouse model of prostate cancer, suggesting a role in the later tumor stages. However, Hepsin protein levels are already high in pre-cancerous lesions and remain elevated in the carcinoma and metastasis stages. In this study, we investigated the role of Hepsin in primary tumor growth in an orthotopic prostate cancer model by use of Hepsin-transfected LnCaP cell lines, which also stably expressed luciferase for bioluminescence imaging. The LnCaP-34 cells stably expressed Hepsin protein on the cell surface at about 5-fold higher levels than the LnCaP-17 cells, which only expressed endogenous Hepsin. The higher Hepsin levels on LnCaP-34 correlated with increased Hepsin enzymatic activity towards pro-urokinase type plasminogen activator. 1x106 LnCaP-17 or LnCaP-34 cells were injected into the left anterior lobe of the prostate of SCID-beige mice (20 animals per group) and tumors were analyzed after 16 weeks. We found a higher tumor occurrence (80% vs 58%) and lower body weights (20.8±0.8g vs. 23.5±0.9g; p<0.05) in the LnCaP-34 group compared to the LnCaP-17 group. In addition, animals of the LnCaP-34 group had 2.4-fold higher normalized prostate tissue weights and larger tumors than the LnCaP-17 group (tumor wet weights of 2.12±0.22g and 1.20±0.27g, respectively; p<0.02). Most strikingly, histological examination revealed that the LnCaP-17 tumors were confined to the left anterior lobe of the prostate (7/7 animals), i.e. the lobe where tumor cells were injected at the start of the study, whereas the LnCaP-34 tumors had spread from the left to the right anterior lobes (7/7 animals). These results suggested that Hepsin overexpression endowed LnCaP-34 cells with increased invasive capacity concomitant with enhanced tumor growth. Moreover, the in-vitro proliferation rates of LnCaP-17 and LnCaP-34 cells were identical, indicating that the prostate microenvironment was important in mediating the Hepsin-driven tumor growth. Unlike the differences in primary tumor growth, the occurrence of lung metastatic lesions as determined by ex-vivo bioluminescence imaging was similar in the LnCaP-17 and LnCaP-34 groups (50% vs 44%). This is in agreement with the presence of numerous tumor cell infiltrates in the tumor vasculature in both groups. However, lymph node metastasis was increased in the LnCaP-34 animals (22% vs 0% in LnCaP-17 animals), based on periaortic lymph node bioluminescence imaging at the time of tissue harvest. In conclusion, the finding that Hepsin overexpression enhances invasive tumor growth suggests that elevated Hepsin expression in pre-cancerous lesions and in prostate carcinoma may contribute to tumor invasiveness and growth.
Narasimha Rao Krishnamurthy - One of the best experts on this subject based on the ideXlab platform.
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structure guided discovery of 2 aryl pyridin 2 yl 1h indole derivatives as potent and selective Hepsin inhibitors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Rajeev Goswami, Gerd Wohlfahrt, Olli Törmäkangas, Anu Moilanen, Anirudha Lakshminarasimhan, Jwala Nagaraj, Karthikeyan Narasingapuram Arumugam, Subhendu Mukherjee, Anita R. Chacko, Narasimha Rao KrishnamurthyAbstract:Hepsin, a type II transmembrane serine protease, is upregulated in prostate cancer and known to be involved in the progression of metastasis. Here we report a structure-guided approach, which resulted in the discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective inhibitors of Hepsin. Potent and selective inhibition of Hepsin by compound 8 is likely due to interactions of the amidine group at the S1 site with the cyclohexyl ring from the 2-aryl group projecting towards the S1' site and the tert-hydroxyl group interacting with His57 side-chain as revealed by X-ray crystallography. Compounds 8 and 10, showed Ki of 0.1 μM for Hepsin, and exhibited inhibition of invasion and migration of Hepsin-overexpressing cell line. Compounds described here could serve as useful tool reagents to investigate the role of Hepsin as a potential therapeutic target in cancer.
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Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective Hepsin inhibitors.
Bioorganic & medicinal chemistry letters, 2015Co-Authors: Rajeev Goswami, Gerd Wohlfahrt, Olli Törmäkangas, Anu Moilanen, Anirudha Lakshminarasimhan, Jwala Nagaraj, Karthikeyan Narasingapuram Arumugam, Subhendu Mukherjee, Anita R. Chacko, Narasimha Rao KrishnamurthyAbstract:Hepsin, a type II transmembrane serine protease, is upregulated in prostate cancer and known to be involved in the progression of metastasis. Here we report a structure-guided approach, which resulted in the discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective inhibitors of Hepsin. Potent and selective inhibition of Hepsin by compound 8 is likely due to interactions of the amidine group at the S1 site with the cyclohexyl ring from the 2-aryl group projecting towards the S1' site and the tert-hydroxyl group interacting with His57 side-chain as revealed by X-ray crystallography. Compounds 8 and 10, showed Ki of 0.1 μM for Hepsin, and exhibited inhibition of invasion and migration of Hepsin-overexpressing cell line. Compounds described here could serve as useful tool reagents to investigate the role of Hepsin as a potential therapeutic target in cancer.
Youngjoo Byun - One of the best experts on this subject based on the ideXlab platform.
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Structure-activity relationship studies of dipeptide-based Hepsin inhibitors with Arg bioisosteres.
Bioorganic chemistry, 2020Co-Authors: Hongmok Kwon, Hayoung Jeon, Jaebong Jang, Sang-hyun Son, Kiho Lee, Song-kyu Park, Youngjoo ByunAbstract:Abstract Hepsin is a type II transmembrane serine protease (TTSP) associated with cell proliferation and overexpressed in several types of cancer including prostate cancer (PCa). Because of its significant role in cancer progression and metastasis, Hepsin is an attractive protein as a potential therapeutic and diagnostic biomarker for PCa. Based on the reported Leu-Arg dipeptide-based Hepsin inhibitors, we performed structural modification and determined in vitro Hepsin- and matriptase-inhibitory activities. Comprehensive structure-activity relationship studies identified that the p-guanidinophenylalanine-based dipeptide analog 22a exhibited a strong Hepsin-inhibitory activity (Ki = 50.5 nM) and 22-fold Hepsin selectivity over matriptase. Compound 22a could be a prototype molecule for structural optimization of dipeptide-based Hepsin inhibitors.
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Design and synthesis of dye-conjugated Hepsin inhibitors.
Bioorganic chemistry, 2019Co-Authors: Kyul Kim, Hongmok Kwon, Sang-hyun Son, Doyoung Choi, Taehyeong Lim, Il Minn, Youngjoo ByunAbstract:Abstract Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel Hepsin-targeted imaging probes by conjugating the Hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong Hepsin-inhibitory activities with Ki values of 21 and 22 nM, respectively. Compound 2 showed selective uptake and retention in Hepsin-overexpressing cells. This is the first report of Hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing Hepsin-based imaging probes and be as a prototype molecule in the design of new Hepsin inhibitors.
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Recent Advances of Hepsin-Targeted Inhibitors.
Current medicinal chemistry, 2017Co-Authors: Hongmok Kwon, Sang-hyun Son, Jooyeon Han, Ki Yong Lee, Youngjoo ByunAbstract:Hepsin is a type II transmembrane serine protease (TTSP) that plays a crucial role in cell growth and development. Hepsin is highly expressed in prostate cancer (PCa) and associated with its progression and metastasis. Therefore, it has been considered as an attractive biomarker of PCa. Recently, low molecular weight inhibitors targeting Hepsin have been developed. Based on the key chemical scaffold, they can be classified into four classes: Indolecarboxamidines, benzamidines, peptide-based analogs, and 2,3-dihydro- 1H-perimidines. In this review, we discuss design strategy, structure-activity relationship (SAR), and binding mode of the four classes of Hepsin inhibitors.
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design synthesis and biological evaluation of psma Hepsin targeted heterobivalent ligands
European Journal of Medicinal Chemistry, 2016Co-Authors: Milan Subedi, Il Minn, Yunhye Kim, Jianbo Chen, Yong Woo Jung, Martin G. Pomper, Youngjoo ByunAbstract:Abstract Cell surface biomarkers such as prostate-specific membrane antigen (PSMA) and Hepsin have received considerable attention as targets for imaging prostate cancer (PCa) due to their high cell surface expression in such tumors and easy access for imaging probes. Novel amidine-containing indole analogs (13–21) as Hepsin inhibitors were designed and synthesized. These compounds showed in vitro inhibitory activity against Hepsin with IC50 values from 5.9 to 70 μM. Based on the SAR of amidine-derived analogs, the novel heterobivalent compound 30, targeting both Hepsin and PSMA, was synthesized by linking compound 18 with Lys-urea-Glu, the key scaffold for the specific binding to PSMA, followed by the conjugation of the optical dye SulfoCy7. Compound 30 exhibited inhibitory activities against PSMA and Hepsin, with IC50 values of 28 nM and 2.8 μM, respectively. In vitro cell uptake and preliminary in vivo optical imaging studies of 30 showed selective binding and retention in both PSMA and Hepsin high-expressing PC3/ML-PSMA-HPN cells as compared with low-expressing PC3/ML cells.
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Design, synthesis and biological evaluation of PSMA/Hepsin-targeted heterobivalent ligands
European journal of medicinal chemistry, 2016Co-Authors: Milan Subedi, Il Minn, Yunhye Kim, Jianbo Chen, Yong Woo Jung, Martin G. Pomper, Youngjoo ByunAbstract:Abstract Cell surface biomarkers such as prostate-specific membrane antigen (PSMA) and Hepsin have received considerable attention as targets for imaging prostate cancer (PCa) due to their high cell surface expression in such tumors and easy access for imaging probes. Novel amidine-containing indole analogs (13–21) as Hepsin inhibitors were designed and synthesized. These compounds showed in vitro inhibitory activity against Hepsin with IC50 values from 5.9 to 70 μM. Based on the SAR of amidine-derived analogs, the novel heterobivalent compound 30, targeting both Hepsin and PSMA, was synthesized by linking compound 18 with Lys-urea-Glu, the key scaffold for the specific binding to PSMA, followed by the conjugation of the optical dye SulfoCy7. Compound 30 exhibited inhibitory activities against PSMA and Hepsin, with IC50 values of 28 nM and 2.8 μM, respectively. In vitro cell uptake and preliminary in vivo optical imaging studies of 30 showed selective binding and retention in both PSMA and Hepsin high-expressing PC3/ML-PSMA-HPN cells as compared with low-expressing PC3/ML cells.