US2006068482A1PendingUtilityA1

Taspase1 and methods of use

56
Individually held — no corporate assignee on recordPriority: Oct 27, 2003Filed: Oct 26, 2004Published: Mar 30, 2006
Est. expiryOct 27, 2023(expired)· nominal 20-yr term from priority
Inventors:James HsiehStanley J. KorsmeyerSusan KorsmeyerEmily Cheng
C12N 9/6478
56
PatentIndex Score
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Cited by
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Claims

Abstract

A novel protease, Taspase1, is described. Taspase1 is involved in the cleavage of the MLL protein, which is required for proper HOX gene regulation. Diagnostic methods utilizing Taspase1 are provided, as well as inhibitors of Taspase1. Methods of using the inhibitors of Taspase1 are also described. For example an inhibitor of Taspase1 can be used to treat a cancer, e.g., leukemia, in a subject.

Claims

exact text as granted — not AI-modified
1 . An isolated polypeptide comprising an amino acid sequence which is at least about 80% identical to the amino acid sequence of SEQ ID NO:1.  
     
     
         2 . The polypeptide of  claim 1  further comprising a heterologous polypeptide.  
     
     
         3 . The polypeptide of  claim 1 , wherein the polypeptide cleaves a polypeptide comprising a Asp-Gly-Ala-Asp-Asp (SEQ ID NO:3) or Asp-Gly-Val-Asp-Asp (SEQ ID NO:4) sequence between the Asp and the Gly amino acids of the Asp-Gly-Ala-Asp-Asp (SEQ ID NO:3) or Asp-Gly-Val-Asp-Asp sequence (SEQ ID NO:4).  
     
     
         4 . The polypeptide of  claim 1 , wherein the polypeptide is intramolecularly proteolyzed into a first peptide fragment and a second peptide fragment.  
     
     
         5 . The polypeptide of  claim 4 , wherein one of the first or second peptide fragments comprises a threonine at the N-terminus.  
     
     
         6 . The polypeptide of  claim 1 , the polypeptide comprising a conserved Leu-Asp-Thr-Val-Gly (SEQ ID NO:5) motif.  
     
     
         7 . The polypeptide of  claim 1 , wherein amino acids 232-236 are Leu-Asp-Thr-Val-Gly (SEQ ID NO:5).  
     
     
         8 . An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:1, wherein up to 20 amino acids are substituted.  
     
     
         9 . An isolated polypeptide encoded by a nucleic acid that hybridizes under high stringency conditions to the nucleic acid of SEQ ID NO:2.  
     
     
         10 . A host cell comprising the polypeptide of  claim 1 .  
     
     
         11 . A method for producing the polypeptide of  claim 1 , the method comprising culturing the host cell of  claim 10  under conditions in which the nucleic acid encoding the polypeptide of  claim 1  is expressed.  
     
     
         12 . An antibody that binds selectively to the polypeptide of  claim 1 .  
     
     
         13 . An inhibitor of the polypeptide of  claim 1 .  
     
     
         14 . The inhibitor of  claim 13 , wherein the inhibitor comprises a polypeptide.  
     
     
         15 . The inhibitor of  claim 14 , the polypeptide comprising the amino acid sequence Ser-Gln-Leu-Ala (SEQ ID NO:6), Ile-Ser-Gln-Leu-Ala (SEQ ID NO:7) or Lys-Ile-Ser-Gln-Leu-Ala (SEQ ID NO:8).  
     
     
         16 . The inhibitor of  claim 14 , the polypeptide comprising the amino acid sequence Ser-Gln-Leu-Asp-aldehyde (SEQ ID NO:9), Ile-Ser-Gln-Leu-Asp-aldehyde (SEQ ID NO:10), or Lys-Ile-Ser-Gln-Leu-Asp-aldehyde (SEQ ID NO:11).  
     
     
         17 . The inhibitor of  claim 14 , the polypeptide comprising Ser-Gln-Leu-Asp-chloromethylketone (SEQ ID NO:12), Ile-Ser-Gln-Leu-Asp-chloromethylketone (SEQ ID NO:13), or Lys-Ile-Ser-Gln-Leu-Asp-chloromethylketone (SEQ ID NO:14).  
     
     
         18 . The inhibitor of  claim 13 , comprising a peptidomimetic of Ser-Gln-Leu-Ala (SEQ ID NO:6), Ile-Ser-Gln-Leu-Ala (SEQ ID NO:7) or Lys-Ile-Ser-Gln-Leu-Ala (SEQ ID NO:8).  
     
     
         19 . The inhibitor of  claim 13 , comprising a peptidomimetic of Ser-Gln-Leu-Asp-aldehyde (SEQ ID NO:9), Ile-Ser-Gln-Leu-Asp-aldehyde (SEQ ID NO:10), or Lys-Ile-Ser-Gln-Leu-Asp-aldehyde (SEQ ID NO:11).  
     
     
         20 . The inhibitor of  claim 13 , comprising a peptidomimetic of Ser-Gln-Leu-Asp-chloromethylketone (SEQ ID NO:12), Ile-Ser-Gln-Leu-Asp-chloromethylketone (SEQ ID NO:13), or Lys-Ile-Ser-Gln-Leu-Asp-chloromethylketone (SEQ ID NO:14).  
     
     
         21 . A method of treating a subject comprising administering to the subject an inhibitor of any of claims  13 - 20 .  
     
     
         22 . The method of  claim 21 , further comprising administering an additional therapeutic agent.  
     
     
         23 . A method of treating cancer in a subject comprising administering to the subject an inhibitor of any of claims  13 - 20 .  
     
     
         24 . The method of  claim 23 , further comprising administering an additional therapeutic agent.  
     
     
         25 . The method of  claim 24 , wherein the therapeutic agent is an anti-cancer agent.  
     
     
         26 . The method of  claim 23 , wherein the cancer is a hematopoietic neoplasm or a solid cancer.  
     
     
         27 . The method of  claim 23 , wherein the cancer is a leukemia.  
     
     
         28 . A method of identifying an inhibitor of the polypeptide of  claim 1 , the method comprising: 
 providing the polypeptide of  claim 1;     contacting the polypeptide of  claim 1  with a candidate inhibitor and a proteolytic substrate;    measuring proteolysis of the substrate in the presence of the candidate inhibitor, and    comparing the proteolysis of the substrate in the presence of the candidate inhibitor to the proteolysis of the substrate in the absence of the candidate inhibitor, wherein a decrease in proteolytic activity identifies the candidate inhibitor as an inhibitor.    
     
     
         29 . The method of  claim 28 , wherein the polypeptide is provided in vivo.  
     
     
         30 . The method of  claim 28 , wherein the polypeptide is provided in vitro.  
     
     
         31 . The method of  claim 28 , wherein the substrate is a Taspase1 substrate.  
     
     
         32 . The method of  claim 28 , wherein the substrate comprises a CS1-like or CS2-like motif.  
     
     
         33 . The method of  claim 28 , wherein the substrate is a polypeptide comprising a fragment of MLL comprising one or more of a CS1, CS2, Ile-Ser-Gln-Leu-Asp (SEQ ID NO:15) or Glu-Gly-Gln-Val-Asp (SEQ ID NO:16) motif.  
     
     
         34 . The method of  claim 28 , wherein the method is performed in an array format.  
     
     
         35 . The method of  claim 28 , further comprising generating a dataset correlating a value for the measured function with the determination of whether the agent is an inhibitor of the polypeptide of  claim 1 .  
     
     
         36 . A method of treating a subject comprising administering to the subject an inhibitor identified in any of claims  28 - 35 .  
     
     
         37 . A method of treating cancer in a subject comprising administering to the subject an inhibitor identified in any of claim  28 - 35 .  
     
     
         38 . The method of  claim 37 , wherein the cancer is a solid tumor.  
     
     
         39 . The method of  claim 37 , wherein the cancer is leukemia.  
     
     
         40 . A method of treating a heomatopoetic proliferative disorder in a subject comprising administering to the subject an inhibitor identified in any of claim  28 - 35 .  
     
     
         41 . An inhibitor identified in any of claims  28 - 35 .

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