Table 1.
A summary of the bisubstrate and bivalent inhibitors of protein kinases described in this review.
| Kinase | Specificity | Ligand A (active-site directed) | Fold Inc Over A | Ligand B | Fold Inc Over B | Linker | Reference |
|---|---|---|---|---|---|---|---|
| PKA/PKC | Ser/Thr | isoquinolinylsulfonyl | 670/67 | Ser-Arg6 (substrate site) | N/A | -NH[CH2]2NH[CH2]2CO- | Ricouart et al. (1991) |
| PKCS | Ser/Thr | bisindolyl maleimide | >43 | CREB peptide (substrate site) | >43 | alkylated Arg | van Ameijde et al. (2010) |
| PKC0 | Ser/Thr | bisindolyl maleimide | 17 | CREB peptide (substrate site) | >58 | alkylated Arg | van Ameijde et al. (2010) |
| PKA | Ser/Thr | ATPγS | N/R | Kemptide (substrate site) | N/R | acetyl | Hines and Cole (2004) |
| PKA | Ser/Thr | indolocarbazole | 0.038 | PKA specificity epitope of PKI (substrate site) | 32 | -NH[CH2]6NHCOCH2- | Schneider et al. (2005) |
| PKA | Ser/Thr | AdoC | 1200 | Arg6 (substrate site) | >830 | -NH(CH2)5C(O)- | Loog et al. (1999) |
| cIRK | Tyr | ATPγS | 310 | IRS727 peptide (substrate site) | N/R | acetyl | Parang et al. (2001) |
| CSK | Tyr | ATPγS | N/R | SRC (aa83-524) (substrate site) | > 17 | -CONH-CQ-Aph-NHCOCH2S- | Shen and Cole (2003) |
| JNK1 | Ser/Thr | indazole | 20000 | JIP1-derived peptide (docking site) | > 70000 | -NH[CH2]3CONH-GlyGly- | Stebbins et al. (2011) |
| JNK1 | Ser/Thr | indazole | 780 | JIP1 TAT peptide (docking site) | > 2700 | -NH[CH2]3CONH-GlyGly- | Stebbins et al. (2011) |
| PKA | Ser/Thr | staurosporine | 93 | cyclo(CTFRVFGC)G | 22000 | PEG3 | Meyer et al. (2007) |
| SRC | Tyr | EELL-(F5)Phe-amide | 230 | coumarin-pYEEIE (SH2 domain) | N/R | Abu8 | Profit et al. (1999) |
| SRC | Tyr | (Ba)EEEIFGEFDap(Hna) | 48 | pYEEIE (SH2 domain) | 50 | βAla3 | Hah et al. (2006) |
The upper panel shows bisubstrate inhibitors (categorized by kinase specificity), while the bottom panel shows bivalent inhibitors. Fold increase refers to the potency of kinase inhibition. (N/A = not applicable; N/R = not reported)