STAT3 SIGNALING: Anticancer Strategies and Challenges
Table 2
Strategies and Challenges to Therapeutic Intervention into STAT3 Signaling
| Strategy | Targets | Examples | Challenges |
|---|---|---|---|
| Inhibit phosphorylation/activation of STAT3 | EGFR agonism TKR activity JAK activity SFK activity |
Cetuximab, panitumumab Gefitinib, erlotinib, lapatinib AG490, LS-104, ICNB1824, CEP-701 Dasatinib, AZD0530, bosutinib |
Modest efficacy; development of resistance; myelosuppression, GI toxicity, and adverse events; kinase selectivity and cardiovascular toxicity |
| Inhibit intermolecular interactions that involve STAT3 | STAT3 SH-2 domains | Oligopeptides designed from EGFR, gp130, and other receptor or pY-containing peptides; peptide aptamers; G-quartet oligonucleotides; small-molecule peptidomimetics | Poor cell permeability and efficacy; poor metabolic stability; poor selectivity for specific SH2 domains; potential for adverse events |
| Inhibit nuclear import/export of STAT3 | Importins α3, α 5, α 7 Importin β Exportin 1 |
Karyostatin 1A (effect on STAT3 undetermined) Leptomycin B and Ratjadone A |
Multicomponent nature of nuclear pore and translocation not fully determined; specificity for translocated proteins problematic |
| Inhibit STAT3-mediated transcription | DNA binding site of STAT3 | dsODN decoys; peptide aptamers | Poor cell permeability without effective and specific delivery systems; poor metabolic stability |
| Natural products | Unspecified | Guggulsterone, honokiol, curcumin, resveratrol, flavopiridol, cucurbitacin | Specificity, potency, and efficacy, mechanism of action unknown |
