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Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis.

Tang X, Mahajan SS, Nguyen LT, Béliveau F, Leduc R, Simon JA, Vasioukhin V - Oncotarget (2014)

Bottom Line: 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.These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

ABSTRACT
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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Identification of novel small molecule Hepsin inhibitors(A) Attenuation of Hepsin-dependent proteolytic activity by the lead compound #4 [20] and its derivatives. Purified recombinant Hepsin was preincubated with 2 μM of the indicated compounds for 30 min. The residual percent activity of the enzyme toward the chromogenic substrate was determined using a microplate reader at 405 nm. Data are the means of three independent experiments ±SD. (B) IC50 determination for Hepsin inhibitors #4, HepIn-1, HepIn-8, HepIn-13, HepIn-17, HepIn-20, HepIn-25. Data are the means of three independent experiments ±SD. (C) Chemical structures of identified Hepsin inhibitors.
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Figure 1: Identification of novel small molecule Hepsin inhibitors(A) Attenuation of Hepsin-dependent proteolytic activity by the lead compound #4 [20] and its derivatives. Purified recombinant Hepsin was preincubated with 2 μM of the indicated compounds for 30 min. The residual percent activity of the enzyme toward the chromogenic substrate was determined using a microplate reader at 405 nm. Data are the means of three independent experiments ±SD. (B) IC50 determination for Hepsin inhibitors #4, HepIn-1, HepIn-8, HepIn-13, HepIn-17, HepIn-20, HepIn-25. Data are the means of three independent experiments ±SD. (C) Chemical structures of identified Hepsin inhibitors.

Mentions: We have previously identified several small molecule compounds that inhibit the activity of purified recombinant Hepsin [20]. To develop and analyze therapeutically-relevant Hepsin inhibitor, we analyzed all available from ChemBridge derivatives of the lead compound #4 (Figure 1). In these studies we used recombinant human Hepsin produced in Drosophila S2 cells [21] (Figure S2). While the majority of these compounds either did not show inhibition or inhibited Hepsin with decreased potency, six compounds (HepIn-1, HepIn-8, HepIn-13, HepIn-17, HepIn-20 and HepIn-25) displayed similar or increased potency (Figure 1, A-B). IC50 values were determined by titration against Hepsin activity and HepIn-13 was found to be the most potent inhibitor with an IC50 of 0.33 μM. (Figure 1, B). Similarly to compound #4, the identified derivatives were specific for Hepsin, as they showed only minor activity against Matriptase, a serine protease highly similar to Hepsin (Figure S3).


Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis.

Tang X, Mahajan SS, Nguyen LT, Béliveau F, Leduc R, Simon JA, Vasioukhin V - Oncotarget (2014)

Identification of novel small molecule Hepsin inhibitors(A) Attenuation of Hepsin-dependent proteolytic activity by the lead compound #4 [20] and its derivatives. Purified recombinant Hepsin was preincubated with 2 μM of the indicated compounds for 30 min. The residual percent activity of the enzyme toward the chromogenic substrate was determined using a microplate reader at 405 nm. Data are the means of three independent experiments ±SD. (B) IC50 determination for Hepsin inhibitors #4, HepIn-1, HepIn-8, HepIn-13, HepIn-17, HepIn-20, HepIn-25. Data are the means of three independent experiments ±SD. (C) Chemical structures of identified Hepsin inhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4012739&req=5

Figure 1: Identification of novel small molecule Hepsin inhibitors(A) Attenuation of Hepsin-dependent proteolytic activity by the lead compound #4 [20] and its derivatives. Purified recombinant Hepsin was preincubated with 2 μM of the indicated compounds for 30 min. The residual percent activity of the enzyme toward the chromogenic substrate was determined using a microplate reader at 405 nm. Data are the means of three independent experiments ±SD. (B) IC50 determination for Hepsin inhibitors #4, HepIn-1, HepIn-8, HepIn-13, HepIn-17, HepIn-20, HepIn-25. Data are the means of three independent experiments ±SD. (C) Chemical structures of identified Hepsin inhibitors.
Mentions: We have previously identified several small molecule compounds that inhibit the activity of purified recombinant Hepsin [20]. To develop and analyze therapeutically-relevant Hepsin inhibitor, we analyzed all available from ChemBridge derivatives of the lead compound #4 (Figure 1). In these studies we used recombinant human Hepsin produced in Drosophila S2 cells [21] (Figure S2). While the majority of these compounds either did not show inhibition or inhibited Hepsin with decreased potency, six compounds (HepIn-1, HepIn-8, HepIn-13, HepIn-17, HepIn-20 and HepIn-25) displayed similar or increased potency (Figure 1, A-B). IC50 values were determined by titration against Hepsin activity and HepIn-13 was found to be the most potent inhibitor with an IC50 of 0.33 μM. (Figure 1, B). Similarly to compound #4, the identified derivatives were specific for Hepsin, as they showed only minor activity against Matriptase, a serine protease highly similar to Hepsin (Figure S3).

Bottom Line: 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.These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus