Small molecules blocking histone reader domains

Abstract

The present invention relates to small molecules interfering with the conformational space of the TONSL ARD occupied by the histone H4 tail. These small molecules targets the binding pocket of TONSL encompassing the H4 residues K12-R23 and act by preventing or disrupting the binding of the H4 tail K12-R23 with the TONSL ARD via direct competition or via allosteric disruption of the binding pocket. The present inventors have identified and solved the structure of a histone reader domain of TONSL termed the ARD (ankyrin repeat domain).

1 . An inhibitor of TONSL, wherein said inhibitor inhibits binding of TONSL ARD to histone H4. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The inhibitor according to  claim 1 , wherein the inhibitor is a small molecule, which targets the conformational space of the TONSL ARD occupied by the histone H4 tail encompassing residues K12-R23 and acting to prevent or disrupt the binding of the histone H4 tail K12-R23 with the TONSL ARD via direct competition or via allosteric disruption of the binding pocket. 
     
     
         5 .- 10 . (canceled) 
     
     
         11 . The inhibitor according to  claim 1 , wherein the inhibitor is a peptide or a polypeptide optionally linked to a conjugated moiety. 
     
     
         12 . The inhibitor according to  claim 11 , wherein the inhibitor is a peptide comprising the sequence Arg-His-Xaa-Lys, wherein Xaa may be any amino acid. 
     
     
         13 . (canceled) 
     
     
         14 . The inhibitor according to  claim 11 , wherein the inhibitor is a peptide comprising the sequence Val-Leu-Arg. 
     
     
         15 .- 23 . (canceled) 
     
     
         24 . The inhibitor according to  claim 11 , wherein the amino acid corresponding to Lys20 of SEQ ID NO:23 is unmethylated. 
     
     
         25 . The inhibitor according to  claim 11 , wherein said peptide comprises or consists of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 or SEQ ID NO:22, 
     
     
         26 . The inhibitor according to  claim 11 , wherein said peptide comprises or consists of amino acids 512 to 692 of SEQ ID NO:16. 
     
     
         27 . The inhibitor according to  claim 11 , wherein the C-terminal of the peptide is amidated or aikylated and/or the N-terminal of the peptide is acetylated or formylated. 
     
     
         28 . (canceled) 
     
     
         29 . The inhibitor according to  claim 11 , wherein said conjugated moiety is a polymeric molecule, such as polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). 
     
     
         30 . The inhibitor according to  claim 1 , wherein the inhibitor is a compound having a 3-[(3-Aminocyclopentyl)carbonyl]-1H-quinolin-4-one core. 
     
     
         31 . The inhibitor according to  claim 1 , wherein the TONSL ARD is identified as amino acids 512-692 of TONSL of SEQ ID NO:16. 
     
     
         32 . The inhibitor according to  claim 1 , wherein histone H4 is is histone H4 of SEQ ID NO:23 or histone H4 of SEQ ID NO:34. 
     
     
         33 . The inhibitor according to  claim 4 , wherein the K12-R23 of the histone H4 tail corresponds to amino acids 12 to 23 of SE Q ID NO:34. 
     
     
         34 . A method of treatment of a clinical condition, said method comprising admintstering a therapeutically effective amount of the inhibitor according to  claim 1  to an individual in need thereof. 
     
     
         35 . A method of treatment of cancer, said method comprising administering a therapeutically effective amount of the inhibitor according to claim to an individual in need thereof. 
     
     
         36 .- 46 . (canceled) 
     
     
         47 . An isolated polynucleotide or amino acid sequence having at least 90% sequence identity to any of SEQ ID NO 1-22. 
     
     
         48 . A TONSL mutant polypeptide comprising at least one mutation in an amino acid of the histone H4 tail binding surface of the TONSL ARD, wherein said TONSL mutant polypeptide apart from said mutation is identical to SEQ ID NO:16 or shares a sequence identity with SEQ ID NO:16 of at least 70%, wherein said TONSL mutant polypeptide is capable of binding MMS22L and wherein said TONSL mutant does not bind histone H4. 
     
     
         49 . The polypeptide according to  claim 48  wherein said TONSL mutant polypeptide carries a mutation in one or more of the amino acids selected from the group consisting of: Glu530, Asp559, Trp563, Glu568, Gln571 and D604, 
     
     
         50 . The polypeptide according to  claim 48 , wherein the polypeptide comprises or consists of a sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO 21 and SEQ NO:22, 
     
     
         51 .- 63 . (canceled)