Table 3.
Potential therapeutic targets in Rapidly Progressive SSc.
| Drug | Target | Mechanism |
|---|---|---|
| TGF-β pathway inhibitors | ||
| Anti-CTGF antibody | CTGF (CCN2) | CTGF (CCN2) is potently induced by TGF-β; Considered crucial in various fibrotic conditions. |
| Pirfenidone | TGF-β | |
| NOX-4 inhibitor | NOX-4 | CTGF inhibition has potential as an anti-fibrotic therapy |
| Exact mechanism of action unknown. | ||
| Suggested effect blocking TGF-β induced fibrosis pathways | ||
| NOX-4 is induced by TGF-β and displays potent profibrotic effects | ||
| Fresolimumab | TGF-β 1,2,3 | Inhibits the three TGF-β isoforms and blocks their profibrotic effects |
| Monoclonal Antibodies | ||
| Rituximab | B-cells | Chimeric monoclonal antibody recognizes B-cell surface protein CD20. Blocks B-cell role in SSc pathogenesis |
| Tocilizumab | IL-6 | Humanized monoclonal antibody against IL-6 receptor. IL-6 plays a profibrotic role in SSc pathogenesis |
| Belimumab | BAFF | Human monoclonal antibody that may modulate BAFF-mediated altered SSc immune responses |
| Lebrikizumab | IL-13Ra1 | Humanized monoclonal antibody against IL-13 receptors. IL-13 induced a profibrotic phenotype in normal dermal fibroblasts |
| Tralokinumab (CAT-354) | IL-13 | Human immunoglobulin Ig G4 monoclonal antibody. IL-13 induced a profibrotic phenotype in normal dermal fibroblasts |
| Tyrosine kinase inhibitors | ||
| Imatinib | c-Abl, PDGF | |
| Nilotinib | c-Abl, PDGF | Inhibit activity of tyrosine kinases mediating |
| Dasatinib | c-Abl, PDGF, Src | pro-fibrotic pathways |
| Nintedanib | VEGF, FGF, PDGF | |
| Non-receptor kinase inhibitors | ||
| Rho-kinase inhibitor | RhoA Kinase | Affects vascular homeostasis. May have direct antifibrotic effects |
| Statins | Rho-A | Inhibit prenylation of Rho-A kinase resulting in inhibition of profibrotic pathways |
| JAK-2 inhibitors | JAK-2 | Jak-2 is involved in stimulation of SSc fibroblasts by TGF-β; JAK-2 inhibition may have a role in antifibrotic therapy in SSc |
| Other signaling pathways | ||
| LPA-1 inhibitors | LPAR | Inhibits LPA-1 implicated in pulmonary fibrosis |
| Rosiglitazone, Pioglitazone | PPAR- γ | PPAR-γ inhibits the fibrogenic effects of TGF-β in vitro; agonists of PPAR-γ may suppress collagen synthesis, myofibroblast differentiation, and other TGF-β induced fibrotic responses |
| Hedgehog signaling | Shh | Has a role in tissue fibrosis through stimulating collagen release and myofibroblast differentiation in vitro and inducing fibrosis in vivo |
| Bortezomib | Proteasome | Proteasome inhibitor; may result in reduced collagen production and increased collagen degradation |
| Wnt inhibitors | Wnt | Wnt plays an important role in various profibrotic pathways |
| Rapamycin | FK binding protein 12 | Binds FK binding protein 12 inhibits mTOR resulting in a diminished SSc immune response in scleroderma. May have direct antifibrotic effects |
| Peptide inhibitors | ||
| Caveolin Scafolding-domain Peptide | CAV-1 | Restores caveolin-1 deficiency in SSc cells- Decreased CAV-1 is a potent pro-fibrotic |
| Endostatin Peptide | Endostatin | Shown to display potent antifibrotic effects in vitro |
| Anti-Thrombin | ||
| Dabigatran | Thrombin | Thrombin is a potential mediator of fibrosis because it is involved in ECM protein deposition, induction of profibrotic factors, and promotion of myofibroblast differentiation |
BAFF: B-cell activation factor
CAV: Caveolin
LPA: Lysophosphatidic Acid
Shh: Sonic hedgehog