US2013273542A1PendingUtilityA1

Detection of gleevec resistance

59
Individually held — no corporate assignee on recordPriority: Oct 5, 2001Filed: Jun 21, 2013Published: Oct 17, 2013
Est. expiryOct 5, 2021(expired)· nominal 20-yr term from priority
Inventors:Brian J. DrukerAmie Corbin
G01N 33/57505G01N 2333/82C12Q 1/6886C12Q 2600/106C07K 14/82C12Q 1/485C12N 9/12
59
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention relates to isolated polypeptides which comprise an amino acid sequence consisting of a mutated functional Abl kinase domain, said mutated functional kinase domain being resistant to inhibition of its tyrosine kinase activity by N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide or a salt thereof, to the use of such polypeptides to screen for compounds which inhibit the tyrosine kinase activity of such polypeptides, to nucleic acid molecules encoding such polypeptides, to recombinant vectors and host cells comprising such nucleic acid molecules and to the use of such nucleic acid molecules in the production of such polypeptides for use in screening for compounds which inhibit the tyrosine kinase activity of such polypeptides.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of detecting STI571 resistance in a subject, comprising:
 selecting a subject undergoing STI571 therapy;   obtaining a sample from the subject;   detecting a mutation in the amino acid sequence of an Abl kinase domain of a Bcr-Abl polypeptide in the sample obtained from the subject compared to position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2, wherein the mutation confers resistance to kinase inhibition by STI571, thereby detecting STI571 resistance in the subject.   
     
     
         2 . The method of  claim 1 , wherein the method comprises detection of an A to T point mutation that results in the substitution of valine for glutamic acid at position 255 or a G to A point mutation that results in the substitution of lysine for glutamic acid at position 255. 
     
     
         3 . The method of  claim 1 , wherein detecting a mutation in the Abl kinase domain of the Bcr-Abl polypeptide comprises:
 determining the sequence of a nucleic acid encoding the Abl kinase domain of the Bcr-Abl polypeptide in the sample obtained from the subject; and   comparing the amino acid sequence encoded by the nucleic acid with the amino acid sequence set forth as SEQ ID NO: 2;   wherein a difference in the amino acid sequence of the Abl kinase domain of the Bcr-Abl polypeptide from the sample obtained from the subject compared to position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2 detects an STI571 resistant Abl kinase domain polypeptide.   
     
     
         4 . The method of  claim 1 , wherein determining the nucleic acid sequence comprises reverse transcriptase polymerase chain reaction. 
     
     
         5 . The method of  claim 1 , wherein determining the nucleic acid sequence comprises DNA sequencing. 
     
     
         6 . The method of  claim 1  wherein the subject has a tumor. 
     
     
         7 . The method of  claim 6 , wherein the tumor is a leukemia. 
     
     
         8 . The method of  claim 1 , wherein detecting a mutation in an Abl kinase domain of the Bcr-Abl polypeptide comprises:
 determining the sequence of an Abl kinase domain in a sample from the subject; and   comparing the amino acid sequence of the Abl kinase domain with position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2,   wherein a difference in the amino acid sequence of the Abl kinase domain from the sample from position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2 detects the STI571 resistant Abl kinase domain polypeptide.   
     
     
         9 . The method of  claim 8 , wherein the substitution is a substitution of valine for glutamic acid or lysine for glutamic acid at position 255. 
     
     
         10 . The method of  claim 8 , wherein the subject has a tumor. 
     
     
         11 . The method of  claim 10 , wherein the tumor is a leukemia. 
     
     
         12 . A method of detecting a STI571 resistant mutation in a subject, comprising:
 selecting a subject for possible treatment with STI571;   obtaining a sample from the subject;   detecting a mutation in an amino acid sequence of the Abl kinase domain of a Bcr-Abl polypeptide in the sample obtained from the subject compared to position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2, wherein the mutation confers resistance to kinase inhibition by STI571, thereby detecting an STI571 resistant mutation in the subject.   
     
     
         13 . The method of  claim 12 , wherein the substitution is a substitution of valine for glutamic acid or lysine for glutamic acid at position 255. 
     
     
         14 . The method of  claim 12 , wherein detecting a mutation in an Abl kinase domain of the Bcr-Abl polypeptide, comprises:
 determining the sequence of the Abl kinase domain in the sample from the subject; and   comparing the amino acid sequence of the Abl kinase domain in the sample with position 255 of Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2,   wherein a difference in the amino acid sequence of the Abl kinase domain from the sample from position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2 indicates the presence of mutant Abl kinase domain polypeptide in the subject.   
     
     
         15 . The method of  claim 12 , wherein the subject has a tumor. 
     
     
         16 . The method of  claim 15 , wherein the tumor is a leukemia. 
     
     
         17 . The method of  claim 16 , wherein the leukemia is myelogenous leukemia. 
     
     
         18 . The method of  claim 14 , wherein the subject is undergoing STI571 therapy and the method is used to detect the presence of the STI571 resistant Abl kinase domain mutation prior to clinical relapse. 
     
     
         19 . The method of  claim 7 , wherein the leukemia is myelogenous leukemia. 
     
     
         20 . The method of  claim 11 , wherein the leukemia is myelogenous leukemia. 
     
     
         21 . The method of  claim 1 , wherein detecting the mutation in the amino acid sequence of the Abl kinase domain of the Bcr-Abl polypeptide in the sample compared to position 255 of the Abl kinase domain of the amino acid sequence set forth as SEQ ID NO: 2 detects STI571 resistance in the subject prior to clinical relapse of the subject during STI571 therapy.

Join the waitlist — get patent alerts

Track US2013273542A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.