Kinesin-like proteins and methods of use

Abstract

The invention relates to methods and compounds for treating subjects who have proliferative disorders. The invention also relates to screening methods for identifying such compounds. The methods and compositions target the activity of the human kinesin-like protein KIF18A (and the KIF18A ortholog, KLP67A) and homologs thereof, and a gene encoding KIF18A or a homologous or orthologous gene. KIF18A and KLP67A are kinesin superfamily (KIF) proteins. Members of the KIF protein family are known to participate in chromosomal and spindle movements during mitosis and meiosis thereby making them attractive targets for treating cancers and the like.

1 . A method for modulating expression or activity of a KIF18A polypeptide, the method comprising: 
 a) contacting a KIF18A nucleic acid with a modulating agent in a concentration sufficient to modulate transcription of the nucleic acid;    b) contacting a cell expressing a KIF18A nucleic acid with a modulating agent in a concentration sufficient to modulate translation from an RNA encoded by the nucleic acid; or    c) contacting a cell expressing the KIF18A polypeptide with a compound that binds to the polypeptide in a concentration sufficient to modulate the activity of the polypeptide.    
     
     
         2 . The method of  claim 1 , wherein the method comprises: a) contacting a KIF18A nucleic acid with a modulating agent in a concentration sufficient to modulate transcription of the nucleic acid.  
     
     
         3 . The method of  claim 2 , wherein the modulating agent is an antisense nucleic acid molecule or a small inhibitory RNA (siRNA).  
     
     
         4 . The method of  claim 1 , wherein the method comprises: b) contacting a cell expressing a KIF18A nucleic acid with a modulating agent in a concentration sufficient to modulate translation from an RNA encoded by the nucleic acid.  
     
     
         5 . The method of  claim 4 , wherein the modulating agent is an antisense nucleic acid molecule or a small inhibitory RNA (siRNA).  
     
     
         6 . The method of  claim 5 , wherein the antisense nucleic acid molecule is complementary to a segment of contiguous nucleotides of a KIF18A nucleotide sequence ranging from a length of 10 to 1000 nucleotides.  
     
     
         7 . The method of  claim 5 , wherein the siRNA comprises the sequence of SEQ ID NO:14, or a fragment thereof.  
     
     
         8 . The method of  claim 1 , wherein the method comprises: c) contacting a cell expressing the KIF18A polypeptide with a compound that binds to the polypeptide in a concentration sufficient to modulate the activity of the polypeptide.  
     
     
         9 . The method of  claim 8 , wherein the compound is an antibody.  
     
     
         10 . The method of  claim 9 , wherein the antibody specifically binds to a KIF18A polypeptide, or a fragment or an allelic variant thereof.  
     
     
         11 . A method for modulating expression or activity of a KIF18A polypeptide, the method comprising: 
 a) contacting a KIF18A nucleic acid comprising a sequence at least 95% identical to SEQ ID NO:1 with a modulating agent in a concentration sufficient to modulate transcription of the nucleic acid;    b) contacting a cell expressing a KIF18A nucleic acid comprising a sequence at least 95% identical to SEQ ID NO:1 with a modulating agent in a concentration sufficient to modulate translation from an RNA encoded by the nucleic acid; or    c) contacting a cell expressing the KIF18A polypeptide comprising a sequence at least 95% identical to SEQ ID NO:2 with a compound that binds to the polypeptide in a concentration sufficient to modulate the activity of the polypeptide.    
     
     
         12 . The method of  claim 11 , wherein the method comprises: a) contacting a KIF18A nucleic acid comprising a sequence at least 95% identical to SEQ ID NO:1 with a modulating agent in a concentration sufficient to modulate transcription of the nucleic acid.  
     
     
         13 . The method of  claim 12 , wherein the modulating agent is an antisense nucleic acid molecule or a small inhibitory RNA (siRNA).  
     
     
         14 . The method of  claim 11 , wherein the method comprises: b) contacting a cell expressing a KIF18A nucleic acid comprising a sequence at least 95% identical to SEQ ID NO:1 with a modulating agent in a concentration sufficient to modulate translation from an RNA encoded by the nucleic acid.  
     
     
         15 . The method of  claim 14 , wherein the modulating agent is an antisense nucleic acid molecule or a small inhibitory RNA (siRNA).  
     
     
         16 . The method of  claim 15 , wherein the antisense nucleic acid molecule is complementary to a segment of contiguous nucleotides of a KIF18A nucleotide sequence ranging from a length of 10 to 1000 nucleotides.  
     
     
         17 . The method of  claim 15 , wherein the siRNA comprises the sequence of SEQ ID NO: 14, or a fragment thereof.  
     
     
         18 . The method of  claim 11 , wherein the method comprises: c) contacting a cell expressing the KIF18A polypeptide comprising a sequence at least 95% identical to SEQ ID NO:2 with a compound that binds to the polypeptide in a concentration sufficient to modulate the activity of the polypeptide.  
     
     
         19 . The method of  claim 18 , wherein the compound is an antibody.  
     
     
         20 . The method of  claim 19 , wherein the antibody specifically binds to a KIF18A polypeptide, or a fragment or an allelic variant thereof.