Table 1.
Examples of small molecule modulators of cytokine function
| Target protein |
Small molecule |
Effects of target modulation on immune cell function |
Approval status |
|---|---|---|---|
| Kinases and phosphatases | |||
| mTOR | rapamycin | Inhibits T and B cell activation; promotes Treg differentiation [14] |
Approved for suppression of transplant rejection |
| Calcineurin | Cyclosporine A; FK506 |
Inhibits NFAT-mediated IL-2 production [15] |
Approved for suppression of transplant rejection |
| JAK3 | Tofacitinib [19] |
Inhibits cytokine via receptors using the common gamma chain (γc) [18] |
Approved for RA |
| SGK1 | GSK650394 [57] |
Inhibits IL-17A production and other phenotypes in salt-induced TH17 cells [29,30]. |
Pre-clinical |
| Lyp/PTPN22 | LTV-1 [58] | Potentiates T and B cell responses [58,59] | Pre-clinical |
| PIKfyve | Apilimod [32] | Inhibits TLR-induced IL-12p40 production [31,32] |
Phase II for Crohn’s Disease; Phase I for Psoriasis |
| SIK2 | HG-9-91-01 [21] |
Potentiates IL-10 production [21,22] | Pre-clinical |
| IRAK1 | IRAK1/4inh [60] |
Inhibits virus-stimulated interferon production [61] |
Pre-clinical |
| LRRK2 | GNE-7915 and others [62] |
Reducing LRRK2 levels suppresses inflammatory cytokine production [26,27] |
Pre-clinical |
| Chromatin modulators | |||
| HDACs | TSA, SAHA and others [63] |
Inhibits inflammatory cytokine production; increase Treg survival/function [64] |
Pre-clinical |
| JMJD3 and UTX |
GSK-J4 [44] | Inhibits inflammatory cytokine production [44] |
Pre-clinical |
| BET proteins | (+)-JQ1, I- BET762 and others [49] |
Inhibits inflammatory cytokine production [65] [50] [51] [52] |
Pre-clinical; phase II for type 2 diabetes (I- BET762) |
| RORγt | Digoxin, SR1001 and others [38,39] |
Inhibits TH17 cells differentiation [38,39] | Pre-clinical |
| AhR | TCDD, kynurenines and others [41,42] |
Stimulates IL-10 production; promotes Treg differentiation [41,42] |
Pre-clinical |
| RAR | ATRA and others |
Promotes Treg differentiation; inhibits TH17 cell differentiation [40] |
Pre-clinical |
| Proteases | |||
| Caspase-1 | VX-765 [66] | Inhibits proteolytic processing of IL-1β and iL-18 to secreted forms [67] |
Phase I for Muckle- Wells syndrome; Phase II for psoriasis |
| Immuno- proteasome |
ONX 0914 and others [68] |
Inhibits antigen processing and inflammatory cytokine production (IL-23; IFNγ; IL-2) [69]. |
Pre-clinical |
| Regulators of second messengers | |||
| PDE4 | Apremilast and others [24] |
Inhibits cAMP degradation [70] | Approved for psoriatic arthritis |
| Receptors | |||
| Toll-like receptors |
Rintatolimod (TLR3) [71]; imiquimod (TLR7) [72]; IMO-2125 (TLR9) [73] |
Stimulates inflammatory cytokine production (e.g. type I IFNs) [16]. |
Phase II for HIV infection (Rintatolimod); Approved for treatment of skin disorders (imiquimod); phase I for Hepatitis C (IMO-2125) |
| IL-2/IL-2R | SP-4206 and others [74] |
Inhibit IL-2 binding to IL-2R [75] | Pre-clinical |
| Prostanoid receptors |
EP4 selective agonists [10] |
Stimulates intracellular cAMP levels [22] | Phase II for ulcerative colitis |