title: Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model.
abstract: Proteolytic activity is required for several key processes in cancer development and progression, including tumor growth, invasion and metastasis. Accordingly, high levels of protease expression and activity have been found to correlate with malignant progression and poor patient prognosis in a wide variety of human cancers. Members of the papain family of cysteine cathepsins are among the protease classes that have been functionally implicated in cancer. Therefore, the discovery of effective cathepsin inhibitors has considerable potential for anti-cancer therapy. In this study we describe the identification of a novel, reversible cathepsin inhibitor, VBY-825, which has high potency against cathepsins B, L, S and V. VBY-825 was tested in a pre-clinical model of pancreatic islet cancer and found to significantly decrease tumor burden and tumor number. Thus, the identification of VBY-825 as a new and effective anti-tumor drug encourages the therapeutic application of cathepsin inhibitors in cancer.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Benelita Tina
authors.initials: BT
authors.lastname: Elie
authors.forename: Vasilena
authors.initials: V
authors.lastname: Gocheva
authors.forename: Tanaya
authors.initials: T
authors.lastname: Shree
authors.forename: Stacie A
authors.initials: SA
authors.lastname: Dalrymple
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Holsinger
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003521:Cyclopropanes; D006845:Hydrocarbons, Fluorinated; C404948:JPM 565; D011480:Protease Inhibitors; D013450:Sulfones; C555884:VBY-825; D002403:Cathepsins; D007930:Leucine
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