Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors

Hongmok Kwon; YunHye Kim; Kieung Park; Soo An Choi; Sang Hyun Son; Youngjoo Byun

doi:10.1016/j.bmcl.2015.12.023

Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors

Hongmok Kwon, YunHye Kim, Kieung Park, Soo An Choi, Sang Hyun Son, Youngjoo Byun

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting K_i values of 22 nM and 3 nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.

Original language	English (US)
Pages (from-to)	310-314
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2015.12.023
State	Published - Jan 15 2016
Externally published	Yes

Keywords

Dipeptides
Hepsin
Prostate cancer
Serine protease

ASJC Scopus subject areas

Biochemistry
Clinical Biochemistry
Molecular Biology
Molecular Medicine
Organic Chemistry
Drug Discovery
Pharmaceutical Science

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title = "Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors",

abstract = "Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22 nM and 3 nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.",

keywords = "Dipeptides, Hepsin, Prostate cancer, Serine protease",

author = "Hongmok Kwon and YunHye Kim and Kieung Park and Choi, {Soo An} and Son, {Sang Hyun} and Youngjoo Byun",

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doi = "10.1016/j.bmcl.2015.12.023",

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AU - Kwon, Hongmok

AU - Kim, YunHye

AU - Park, Kieung

AU - Choi, Soo An

AU - Son, Sang Hyun

AU - Byun, Youngjoo

PY - 2016/1/15

Y1 - 2016/1/15

N2 - Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22 nM and 3 nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.

AB - Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22 nM and 3 nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.

KW - Dipeptides

KW - Hepsin

KW - Prostate cancer

KW - Serine protease

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Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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