更新于：2024-11-01

hepsin x matriptase x HGFA

更新于：2024-11-01

基本信息

关联

项与 hepsin x matriptase x HGFA 相关的药物

Caramcillin

靶点

HGFA x hepsin x matriptase

作用机制

HGFA 抑制剂 [+2]

在研机构-

原研机构-

在研适应症

细菌感染

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 HGFA 相关的临床结果

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

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

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项与 hepsin x matriptase x HGFA 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.

2024-03-28·Journal of Medicinal Chemistry1区 · 医学

Mechanism-Based Macrocyclic Inhibitors of Serine Proteases

1区 · 医学

Article

作者: Kashipathy, Maithri M ; De Bona, Paolo ; Janetka, James W ; Lovell, Scott ; Banas, Victoria ; Damalanka, Vishnu C ; Battaile, Kevin

Protease inhibitor drug discovery is challenged by the lack of cellular and oral permeability, selectivity, metabolic stability, and rapid clearance of peptides. Here, we describe the rational design, synthesis, and evaluation of peptidomimetic side-chain-cyclized macrocycles which we converted into covalent serine protease inhibitors with the addition of an electrophilic ketone warhead. We have identified potent and selective inhibitors of TMPRSS2, matriptase, hepsin, and HGFA and demonstrated their improved protease selectivity, metabolic stability, and pharmacokinetic (PK) properties. We obtained an X-ray crystal structure of phenyl ether-cyclized tripeptide VD4162 (8b) bound to matriptase, revealing an unexpected binding conformation. Cyclic biphenyl ether VD5123 (11) displayed the best PK properties in mice with a half-life of 4.5 h and compound exposure beyond 24 h. These new cyclic tripeptide scaffolds can be used as easily modifiable templates providing a new strategy to overcoming the obstacles presented by linear acyclic peptides in protease inhibitor drug discovery.

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.