Bisubstrate inhibitors of protein tyrosine kinases as therapeutic agents
A bisubstrate inhibitor of Src kinases, having a nucleotide or N-heteroaromatic moiety; and a peptide/phosphopeptide, peptidomimetic, or phosphopeptide mimic moiety. The moieties are linked by a rigid or a flexible linker. The nucleotide or N-heteroaromatic moiety is ATP, ATP-mimics, N-heteroaromatics including purine-based derivatives, pyrimidine-based derivatives such as 2,4-diamino-5-substituted pyrimidine derivatives, pyrazole[3,4-d]pyrimidine derivatives, pyrrolo[2,3-d]pyrimidine derivatives, pyrido[2,3-d]pyrimidine derivatives, amino-substituted dihydropyrimido[4,5-d]pyrimidinone derivatives, thieno- and furo-substituted derivatives, quinazoline derivatives, and quinoline derivatives, and several natural products such as aminogenistein. The phosphopeptide mimics comprise phosphonate-based phosphotyrosine mimetics such as phosphonomethylphenylalanine (Pmp) and its analogues, carboxylic acid-based phosphotyrosine mimetics such as malonyltyrosine or phenylalanine analogues and their derivatives such as carboxymethyl phenylalanine, uncharged pTyr mimetics, and conformationally constrained peptides. The phosphopeptide or phosphopeptide mimics inhibits the Src kinases SH2 domain.
1. A bisubstrate inhibitor of Src kinases selected from the group consisting of:
wherein CIYKYY is SEQ ID NO: 2.
2. A bisubstrate inhibitor of Src kinases selected from the group consisting of:
3. A bisubstrate inhibitor of Src kinases selected from the group consisting of:
wherein Y is N or CH;
n is 2, 4, 6 or 8; and
CIYKYY is SEQ ID NO: 2.
4. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
5. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
wherein CIYKYY is SEQ ID NO: 2.
6. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
wherein CIYKYY is SEQ ID NO: 2.
7. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
wherein CIYKYY is SEQ ID NO: 2.
8. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
wherein CIYKYY is SEQ ID NO: 2.
9. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
wherein CIYKYY is SEQ ID NO: 2.
10. The bisubstrate inhibitor of Src kinases of claim 1 consisting of
wherein CIYKYY is SEQ ID NO: 2.
11. The bisubstrate inhibitor of Src kinases of claim 2 consisting of
12. The bisubstrate inhibitor of Src kinases of claim 2 consisting of
13. The bisubstrate inhibitor of Src kinases of claim 2 consisting of
14. The bisubstrate inhibitor of Src kinases of claim 2 consisting of
15. The bisubstrate inhibitor of Src kinases of claim 2 consisting of
16. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein CIYKYY is SEQ ID NO: 2.
17. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein Y is N or CH; and
CIYKYY is SEQ ID NO: 2.
18. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein Y is N or CH; and
CIYKYY is SEQ ID NO: 2.
19. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein Y is N or CH;
n is 2, 4, 6 or 8; and
CIYKYY is SEQ ID NO: 2.
20. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein Y is N or CH;
n is 2, 4, 6 or 8; and
CIYKYY is SEQ ID NO: 2.
21. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein Y is N or CH;
n is 2, 4, 6 or 8; and
CIYKYY is SEQ ID NO: 2.
22. The bisubstrate inhibitor of Src kinases of claim 3 consisting of
wherein Y is N or CH;
n is 2, 4, 6 or 8; and
CIYKYY is SEQ ID NO: 2.
23. A composition comprising a bisubstrate inhibitor of Src kinases of claim 1 , 2 , or 3 .
24. A method of making a bisubstrate inhibitor of claim 2 comprising:
assembling the peptide CIYKYY (SEQ ID NO: 2) on solid phase resin using N-(9-fluorenyl)methoxycarbonyl (Fmoc)-based chemistry and Fmoc-protected amino acids or resins in the presence of 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and N-methylmorpholine in DMF as coupling and activating agents, respectively;
reacting the resin-linked peptide with 3-phenylpyrazolpyrimidine-substituted with alkyl- or arylcarboxylic acids in the presence of HBTU and N,N-diisopropylethylamine; and
deprotecting and cleaving from solid support in the presence of TFA/water/anisole/ethanedithiol to afford N-terminal substituted 3-phenylpyrazolpyrimidine-peptide conjugates.