US2005065332A1PendingUtilityA1

Global suppressors of p53 mutations

53
Assignee: UNIV WASHINGTONPriority: Jan 16, 2002Filed: Jan 15, 2003Published: Mar 24, 2005
Est. expiryJan 16, 2022(expired)· nominal 20-yr term from priority
Inventors:Rainer K. Brachmann
C07K 14/4746
53
PatentIndex Score
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Cited by
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Claims

Abstract

The transcription factor and tumor suppressor protein p53 is inactivated in many human cancers. Approximately forty percent of cancers carry large amounts of mutated full-length p53 protein with one of over 900 reported single amino acid changes in the p53 core domain that recognizes p53 DNA binding sites. The ability to restore function to these inactive p53 proteins would dramatically improve cancer therapy. We show that this goal is achievable. Using genetic strategies and p53 assays in the yeast S. cerevisiae and mammalian cells, we identify suppressor mutations that, in the context of the some protein, restore function to some of the most common p53 cancer mutants tested. Crystallographic studies of this general suppressor motif eludicate the structural basis of restoring integrity to the p53 core domain and lead to small compounds that stabilize p53 cancer mutants.

Claims

exact text as granted — not AI-modified
1 . A nucleic acid molecule encoding human p53 which comprises: 
 at least one intragenic suppressor mutation, which is capable of suppressing a mutation of human p53 which occurs in human cancers when said intragenic suppressor and cancer mutations are present in a cis configuration; wherein said at least one intragenic suppressor mutation is selected from the group consisting of:    T81S; A83V; P87R; Q100L; Q100R; Q104P; F113L; L114V; T118M; V122I; C124S; K139R; Q144L; W146R; Q165L; V172I; H178Y; S183T; A189V; F212L; E224G; S227P; S227T; D228N; D228A; D228E; C229W; T230S; T231I; I232V; H233R; H233Y; Y234F; N235K; N235S; Y236N; N239M; N239W; N239L; N239F; N239R; N239H; S240Q; S240T; S240R; D281G; E285G; E285K; E294G; G325R; E343V; E346G; D352G; and combinations thereof.    
     
     
         2 . A nucleic acid molecule encoding human p53 which comprises: 
 a set of at least one intragenic suppressor mutation, wherein said set is capable of suppressing a mutation of human p53 which occurs in human cancers when said intragenic suppressor and cancer mutations are present in a cis configuration; wherein said set is selected from the group consisting of:    F113L;    L114V+T123P+V172I+A189V;    T123P+A189V;    S227P+N239Y;    T118M+H168R;    V122I+C124S+H168R;    T123A+H168R;    K139R+H168R+N239Y;    H168R+T231I;    T123A+S240R;    H178Y+S240R;    D281G+E285G+G325R+E343V;    E285K+D352G;    E285K+E294G+E346G;    T81S+A83V+S240R;    P87R+Q 100L+Q104P+Q144L+S240R;    Q100R+W146R+S240R;    Q165L+F212L+S240R;    S183T+S240R;    E224G+S240R;    S240R;    D228A+N235K+N239M;    D228E+N235K+Y236N+N239L;    I232V+H233R+Y234F+N235K+N239L;    N235K+S240T;    Y234F+N239L;    N235K+N239R;    H233Y+N239Y;    N239F;    N239Y+S240Q;    H233Y+N235K+N239Y;    N235K+N239Y;    N235S+N239Y+S240N;    D228N+N239Y;    N235K+N239W;    D228E+N239Y;    N235K+S240N;    N239W;    T230S+N239Y;    S227T+N235K+N239Y;    H233R+N235S+N239R+S240R;    N239R;    N239R+S240R;    C229W+N239R+S240R;    N239L+S240R;    N239F+S240R;    I232V+N239H+S240R;    D228E+C229W+N235K+N239Y+S240R;    N239Y+S240R; and combinations thereof.    
     
     
         3 . The nucleic acid of  claim 1  further comprising a p53 mutation found in a cancer selected from the group consisting of: G245S; R249S; R273C; R273H; C141Y, V157F, R158L, Y163C, V173L, V173M, Y205C, Y220C, G245C, R249M, V272M, R273L, and E286K.  
     
     
         4 . The nucleic acid of  claim 1  further comprising at least one mutation of human p53 found in a cancer.  
     
     
         5 . The nucleic acid of  claim 2  further comprising a p53 mutation found in a cancer selected from the group consisting of: G245S; R249S; R273C; R273H; C141Y, V157F, R158L, Y163C, V173L, V173M, Y205C, Y220C, G245C, R149M, V272M, R273L, and E286K.  
     
     
         6 . The nucleic acid of  claim 2  further comprising at least one mutation of human p53 found in a cancer.  
     
     
         7 . A human p53 protein which comprises: 
 at least one intragenic suppressor mutation which is capable of suppressing a mutation of human p53 which occurs in human cancers when said intragenic suppressor and said cancer mutations are present in a cis configuration; wherein said intragenic suppressor mutation is selected from the group consisting of:    T81S; A83V; P87R; Q100L; Q100R; Q104P; F113L; L114V; T118M; V122I; C124S; K139R; Q144L; W146R; Q165L; V172I; H178Y; S183T; A189V; F212L; E224G; S227P; S227T; D228N; D228A; D228E; C229W; T230S; T231I; I232V; H233R; H233Y; Y234F; N235K; N235S; Y236N; N239M; N239W; N239L; N239F; N239R; N239H; S240Q; S240T; S240R; D281G; E285G; E285K; E294G; G325R; E343V; E346G; D352G; and combinations thereof.    
     
     
         8 . A human p53 protein which comprises: 
 a set comprising at least one intragenic suppressor mutation which is capable of suppressing a mutation of human p53 which occurs in human cancers when said intragenic suppressor and said cancer mutations are present in a cis configuration; wherein said set is selected from the group consisting of:    F113L;    L114V+T123P+V172I+A189V;    T123P+A189V;    S227P+N239Y;    N239Y;    T118M+H168R;    V122I+C124S+H168R;    T123A+H168R;    K139R+H168R+N239Y;    H168R+T231I;    T123A+S240R;    H178Y+S240R;    D281G+E285G+G325R+E343V;    E285K+D352G;    E285K+E294G+E346G;    T81S+A83V+S240R;    P87R+Q100L+Q104P+Q144L+S240R;    Q100R+W146R+S240R;    Q165L+F212L+S240R;    S183T+S240R;    E224G+S240R;    S240R;    D228A+N235K+N239M;    D228E+N235K+Y236N+N239L;    I232V+H233R+Y234F+N235K+N239L;    N235K+S240T;    Y234F+N239L;    N235K+N239R;    H233Y+N239Y;    N239F;    N239Y+S240Q;    H233Y+N235K+N239Y;    N235K+N239Y;    N235S+N239Y+S240N;    D228N+N239Y;    N235K+N239W;    D228E+N239Y;    N235K+S240N;    N239W;    T230S+N239Y;    S227T+N235K+N239Y;    H233R+N235S+N239R+S240R;    N239R;    N239R+S240R;    C229W+N239R+S240R;    N239L+S240R;    N239F+S240R;    I232V+N239H+S240R;    D228E+C229W+N235K+N239Y+S240R;    N239Y+S240R; and combinations thereof.    
     
     
         9 . The p53 protein of  claim 7  further comprising a p53 mutation found in a cancer selected from the group consisting of: G245S; R249S; R273C; R273H; C141Y, V157F, R158L, Y163C, V173L, V173M, Y205C, Y220C, G245C, R249M, V272M, R273L, and E286K.  
     
     
         10 . The p53 protein of  claim 7  further comprising at least one mutation of human p53 found in a cancer.  
     
     
         11 . The p53 protein of  claim 8  further comprising a p53 mutation found in a cancer selected from the group consisting of: G245S; R249S; R273C; R273H; C141Y, V157F, R158L, Y163C, V173L, I173M, Y205C, Y220C, G245C, R249M, V272M, R273L, and E286K.  
     
     
         12 . The p53 protein of  claim 8  further comprising at least one mutation of human p53 found in a cancer.  
     
     
         13 . A cell comprising the nucleic acid of  claim 1 .  
     
     
         14 . A cell comprising the nucleic acid of  claim 2 .  
     
     
         15 . A cell comprising the nucleic acid of  claim 3 .  
     
     
         16 . A cell comprising the nucleic acid of  claim 4 .  
     
     
         17 . A cell comprising the nucleic acid of  claim 5 .  
     
     
         18 . A cell comprising the nucleic acid of  claim 6 .  
     
     
         19 . A cell comprising the protein of  claim 7   
     
     
         20 . A cell comprising the protein of  claim 8 .  
     
     
         21 . A cell comprising the protein of  claim 9 .  
     
     
         22 . A cell comprising the protein of  claim 10 .  
     
     
         23 . A cell comprising the protein of  claim 11 .  
     
     
         24 . A cell comprising the protein of  claim 12 .  
     
     
         25 . A human p53 polypeptide which comprises: 
 a portion of human p53 protein, said portion comprising residues 94 to 292, and at least one intragenic suppressor mutation which is capable of suppressing a mutation of human p53 which occurs in human cancers when said intragenic suppressor and said cancer mutations are present in a cis configuration; wherein said intragenic suppressor mutation is selected from the group consisting of:    T81S; A83V; P87R; Q100L; Q100R; Q104P; F113L; L114V; T118M; V122I; C124S; K139R; Q144L; W146R; Q165L; V172I; H178Y; S183T; A189V; F212L; E224G; S227P; S227T; D228N; D228A; D228E; C229W; T230S; T231 I; I232V; H233R; H233Y; Y234F; N235K; N235S; Y236N; N239M; N239W; N239L; N239F; N239R; N239H; S240Q; S240T; S240R; D281G; E285G; E285K; E294G; G325R; E343V; E346G; D352G; and combinations thereof.    
     
     
         26 . A human p53 polypeptide which comprises: 
 a portion of human p53 protein, said portion comprising residues 94 to 292, and a set of at least one intragenic suppressor mutation, wherein said set is capable of suppressing a mutation of human p53 which occurs in human cancers when said mutation is present in a cis configuration to the cancer mutation; wherein said set is selected from the group consisting of:    F113L;    L114V+T123P+V172I+A189V;    T123P+A189V;    S227P+N239Y;    N239Y;    T118M+H168R;    V122I+C124S+H168R;    T123A+H168R;    K139R+H168R+N239Y;    H168R+T231I;    T123A+S240R;    H178Y+S240R;    D281G+E285G+G325R+E343V;    E285K+D352G;    E285K+E294G+E346G;    T81S+A83V+S240R;    P87R+Q100L+Q104P+Q144L+S240R;    Q100R+W146R+S240R;    Q165L+F212L+S240R;    S183T+S240R;    E224G+S240R;    S240R;    D228A+N235K+N239M;    D228E+N235K+Y236N+N239L;    I232V+H233R+Y234F+N235K+N239L;    N235K+S240T;    Y234F+N239L;    N235K+N239R;    H233Y+N239Y;    N239F;    N239Y+S240Q;    H233Y+N235K+N239Y;    N235K+N239Y;    N235S+N239Y+S240N;    D228N+N239Y;    N235K+N239W;    D228E+N239Y;    N235K+S240N;    N239W;    T230S+N239Y;    S227T+N235K+N239Y;    H233R+N235S+N239R+S240R;    N239R;    N239R+S240R;    C229W+N239R+S240R;    N239L+S240R;    N239F+S240R;    I232V+N239H+S240R;    D228E+C229W+N235K+N239Y+S240R;    N239Y+S240R; and combinations thereof.    
     
     
         27 . The p53 polypeptide of  claim 25  further comprising a p53 mutation found in a cancer selected from the group consisting of: G245S; R249S; R273C; R273H; C141Y, V157F, R158L, Y163C, V173L, V173M, Y205C, Y220C, G245C, R249M, V272M, R273L, and E286K.  
     
     
         28 . The p53 polypeptide of  claim 25  fer comprising at least one mutation of human p53 found in a cancer.  
     
     
         29 . The p53 polypeptide of  claim 26  further comprising a p53 mutation found in a cancer selected from the group consisting of: G245S: R249S: R273C, R273H; C141Y, V157F, R158L, Y163C, V173L, V173M, Y205C, Y220C, G245C, R249M, V272M, R273L, and E286K.  
     
     
         30 . The p53 polypeptide of  claim 26  further comprising at least one mutation of human p53 found in a cancer.  
     
     
         31 . The p53 polypeptide of  claim 25  which comprises residues 94 to 300.  
     
     
         32 . The p53 polypeptide of  claim 25  which comprises residues 94 to 312.  
     
     
         33 . The p53 polypeptide of  claim 25  which comprises residues 81 to 352.  
     
     
         34 . The p53 polypeptide of  claim 26  which comprises residues 94 to 300.  
     
     
         35 . The p53 polypeptide of  claim 26  which comprises residues 94 to 312.  
     
     
         36 . The p53 polypeptide of  claim 26  which comprises residues 81 to 352.

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