Table 1.
Summary of pre-clinical studies on Th-differentiation targeting TF inhibitors.
| Class | Sub-class | Compound | Target | murine aGVHD model | Effect GVHD | Effect GVL | Effect Th differentiation | Reference |
|---|---|---|---|---|---|---|---|---|
| Epigenetic regulators | HDACi (short-chain fatty acid) | Valproic acid (VPA) | AKT | MHC mismatch model: BL/6→BALB/c | ameliorated | preserved | Th1 ↓ Th17 ↓ | (171) |
| HDACi(sirtuin inhibitor) | Ex-527 | Sirt-1 | MHC mismatch model:BL/6→BALB/c | ameliorated | preserved | Th1 ↓ Th17↓ Tregs ↑ | (172) | |
| HDACi(hydroxamic acid) | Vorinostat (SAHA) | STAT3/STAT1 | MHC mismatch model:BL/6→BALB/c | ameliorated | - | - | (173) | |
| HDACi(cyclic peptides) | Romidepsin | STAT3/STAT1 | MLR | ameliorated | - | - | (174, 175) | |
| Kinase inhibitors | JAK/STAT Inhibitors | Ruxolitinib (INCB018424) | JAK1/2 | MHC mismatch model:B6→BALB/c | ameliorated | preserved | Th1 ↓ Th17↓ Tregs↑ | (176, 177) |
| JAK/STAT Inhibitors | Itacitinib (INCB039110) | JAK1 | MHC mismatch model:B6→BALB/c; xenogeneic model |
ameliorated | preserved | Tregs ↑ | (178–180) | |
| JAK/STAT Inhibitors | Pacritinib | JAK2 | minor histocompatibility antigen-mismatched model BALB/b→BALB/c;MLR (human);human skin graft rejection model | ameliorated | preserved | Th1↓ Th17↓ Th2↑ | (181) | |
| JAK/STAT Inhibitors | Pacritinib +S3I-201 +Rapamycin (Sirolismus) | JAK2+STAT3+mTOR | xenograft model | ameliorated | preserved | Th1 ↓only PAC/SIR or S3I/SIR:Th17↓ Tregs↑ | (166) | |
| JAK/STAT Inhibitors | Fedratinib (TG101348) | JAK2/STAT3 axis | MLR | ameliorated | - | Th1↓ Th17↓ Tregs↑ | (182) | |
| JAK/STAT Inhibitors | Tofacitinib (CP-690550) | JAK3 | semiallogeneic MHCII-disparate model B6→(B6xbm12)F1;MLR | ameliorated | - | Th1↓ | (183) | |
| ROCK1/2 Inhibitors | Fausidil | Rho kinase (ROCK1 and ROCK2) | semiallogeneic MHC-disparate modelC3H→ (B6C3)F1 | ameliorated | – | – | (184) | |
| ROCK1/2 Inhibitors | Belomosudil (KD025) | ROCK2 | major MHC mismatch model of multiorgan cGVHD; minor MHC mismatch model of sclerodermous GVHD | ameliorated | – | Tfh ↓ Tfregs↑ | (185) | |
| other Inhibitors | ONO-7790500 | ITK | semiallogeneic MHC-disparate modelB6→ (B6D2)F1 | ameliorated/delayed | preserved | Th1 ↓Th2 ↓ Th17↓ | (186) | |
| other Inhibitors | 6-bromoindirubin 3’-oxime (BIO) | glycogen synthase kinase 3 (GSK3) STAT3STAT1 | xenograft model | prevented | preserved | Th1 ↓Th2 ↓ | (187) | |
| other TF Inhibitors | peptide antibiotic | Echinomycin (NSC-13502) | HIF-1α | MHC mismatch model:B6→BALB/c | ameliorated | preserved | Th1 ↓ Th17↓ Tregs↑ | (188) |
| IT-603 | c-Rel | MHC mismatch model:B6→BALB/c | ameliorated | preserved | - | (189) | ||
| IT-901 | c-Rel | MHC mismatch model:B6→BALB/c | ameliorated | preserved | - | (190) | ||
| syntheticretinoid(SR11302) | AP-1 | MHC mismatch model:B6→BALB/c | ameliorated | - | Th1 ↓ Th17↓ Tregs↑ | (191) | ||
| S3I-201 | STAT3 | MLR (human); human skin graft rejection; xenograft GVHD model; human GVHD | ameliorated | preserved | Th1↓ Th17↓ iTregs↑ | (192–194) | ||
| nitrofuran antibiotic | nifuroxazide | STAT3 | MHC mismatch model:B6→BALB/c | ameliorated | - | Th1↓ Tregs↑ | (195) | |
| bile acid | indirectly RORyt | MHC mismatch model:B6→BALB/c | ameliorated | preserved | Th17 ↓ Treg↑ | (196) | ||
| 3-OxoLC(bile acid) | (197) |