更新于：2024-11-01

hepsin x matriptase x HGF

更新于：2024-11-01

基本信息

关联

项与 hepsin x matriptase x HGF 相关的药物

SRI 31215

靶点

HGF x hepsin x matriptase

作用机制

HGF刺激剂 [+2]

在研机构

Southern Research Institute

原研机构

Southern Research Institute

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 hepsin x matriptase x HGF 相关的临床结果

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100 项与 hepsin x matriptase x HGF 相关的转化医学

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0 项与 hepsin x matriptase x HGF 相关的专利（医药）

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项与 hepsin x matriptase x HGF 相关的文献（医药）

2024-08-01·Protein Science

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin

Article

作者: Damalanka, Vishnu C. ; Helander, Jonathan ; Poreba, Marcin ; Janetka, James W. ; Drag, Marcin ; De Bona, Paolo ; Lovell, Scott ; Kasperkiewicz, Paulina ; O'Donoghue, Anthony J. ; Kashipathy, Maithri M. ; Kooner, Anoopjit S. ; Mahoney, Matthew W. ; Battaile, Kevin P. ; Craik, Charles S. ; Rut, Wioletta ; Norman, Mariah

AbstractInhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS‐SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH‐1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK‐1‐89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X‐ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design.

2021-12-23·Journal of Medicinal Chemistry1区 · 医学

Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression

1区 · 医学

Article

作者: Janetka, James W. ; Damalanka, Vishnu C. ; Primeau, Tina ; Voss, Jorine J. L. P. ; Mahoney, Matthew W. ; Klampfer, Lidija ; Li, Shunqiang

Hepatocyte growth factor (HGF), the ligand for the MET receptor tyrosine kinase, is a tumor-promoting factor that is abundant in the tumor microenvironment. Proteolytic activation of inactive pro-HGF by one or more of the serine endopeptidases matriptase, hepsin, and HGF activator is the rate-limiting step in HGF/MET signaling. Herein, we have rationally designed a novel class of side chain cyclized macrocyclic peptide inhibitors. The new series of cyclic tripeptides has superior metabolic stability and significantly improved pharmacokinetics in mice relative to the corresponding linear peptides. We identified the lead compound VD2173 that potently inhibits matriptase and hepsin, which was tested in parallel alongside the acyclic inhibitor ZFH7116 using both in vitro and in vivo models of lung cancer. We demonstrated that both compounds block pro-HGF activation, abrogate HGF-mediated wound healing, and overcome resistance to EGFR- and MET-targeted therapy in lung cancer models. Furthermore, VD2173 inhibited HGF-dependent growth of lung cancer tumors in mice.

2019-04-01·Future Medicinal Chemistry4区 · 医学

Recent Progress on Inhibitors of the Type II Transmembrane Serine proteases, hepsin, Matriptase and matriptase-2

4区 · 医学

Review

作者: Damalanka, Vishnu C ; Janetka, James W

Members of the type II transmembrane serine proteases (TTSP) family play a vital role in cell growth and development but many are also implicated in disease. Two of the well-studied TTSPs, matriptase and hepsin proteolytically process multiple protein substrates such as the inactive single-chain zymogens pro-HGF and pro-macrophage stimulating protein into the active heterodimeric forms, HGF and macrophage stimulating protein. These two proteases also have many other substrates which are associated with cancer and tumor progression. Another related TTSP, matriptase-2 is expressed in the liver and functions by regulating iron homoeostasis through the cleavage of hemojuvelin and thus is implicated in iron overload diseases. In the present review, we will discuss inhibitor design strategy and Structure activity relationships of TTSP inhibitors, which have been reported in the literature.