Table 1.
Commercially available IKKβ inhibitors.
| Inhibitor | Mechanism | Ki/IC50 for IKKβ (nM) * [Ref] | Selectivity Over IKKα | Known Off-Targets | Bio-Availability | Pre-Clinical Therapeutic Efficacy |
|---|---|---|---|---|---|---|
| BI605906 (BIX02514) | ATP-competitive | 380 [40] | >300 fold (>100 µM) | >300-fold selectivity over 100 representative tyr/ser-thr kinases IGF1 (7.6 µM) | N/A | N/A |
| MLN120B | ATP-competitive | 60 [41] | >1000 fold (>100 µM) | >1000-fold selectivity over 30 representative tyr/ser-thr kinases | Good oral bio-availability | Multiple myeloma [42] Arthritis [43] |
| PHA-408 | ATP-competitive | 10–40 [44,45] | >350 fold (14 µM) | >100-fold selectivity over 30 representative tyr/ser-thr kinases PIM-1 (0.6 µM) | Good oral bio-availability | Arthritis [44] COPD [46,47] |
| TPCA-1 (IKK inhibitor IV) | ATP-competitive | 18 [48] | ~22-fold (400 nM) | STAT3 | Poor oral bio-availabilityAdministered intra-peritoneally | Arthritis [48] Nasal epithelium inflammation [49] Glioma [50] NSCLC [51] COPD [52] Wet AMD [53] |
| SC-514 | ATP-competitive | 3000–12,000 [54] | >15-fold (>200 µM) | CDK2/CycA (61 µM) Aurora A (71 µM) PRAK (75 µM) MSK (123 µM) | Poor oral bio-availabilityAdministered intra-peritoneally | Rat model of inflammation [54] Oral squamous cell carcinoma [55] Osteoclast-related disorders [56] Diabetic neuropathy [57] |
| LY2409881 | ATP-competitive | 30 [58] | > 10-fold | >10-fold selectivity over panel of representative tyr/ser-thr kinases | Administered intra-peritoneally | DLBCL [58] |
| PS-1145 | ATP-competitive | 100 [59,60] | N/A | [61] | Administered intra-peritoneally | Multiple myeloma [61] DLBCL [62] Graft-versus-host disease [60] Tobacco smoke-induced pulmonary inflammation [63] |
| Compound A (Bay 65-1942) | ATP-competitive | Ki for GST-IκBα = 4 nM [64] | >30 fold (135 nM) | IKKε, MKK4, MKK7, ERK-1, Syk, Lck, Fyn, PI3Kγ, PKA and PKC (IC50 > 10 µM) | Good oral bio-availability | KRAS-induced lung cancer [65] Chronic pulmonary inflammation [64] Ischemia–reperfusion injury [66] LPS-induced neurotoxicity [67] |
| IKK-16 (IKK Inhibitor VII) | ATP-competitive | 40–70 [68,69] | 5-fold (200 nM) | LRKK2 (50 nM) | Good oral bio-availability | Multiple organ failure associated with hemorrhagic shock [70] Sepsis-associated multiple organ dysfunction [71] Ventilation-induced lung injury [72] Acute kidney injury [73] |
| IMD-0354 (and pro-drug IMD-1041) | ATP-competitive | ~1µM [74,75] | N/A | N/A | Administered intra-peritoneally | CLL [76] Pancreatic cancer [77] Adult T-cell leukemia [78] Breast cancer [75] |
| ACHP (IKK inhibitor VIII) | ATP-competitive | 8.5 [79] | 30-fold (250 nM) | IKKε, Syk, MKK4 (IC50 > 20 µM) | Good oral bio-availability | Multiple myeloma [80] Adult T-cell leukemia [81] HIV-1 replication [82] |
| BMS-345541 | Allosteric | 300 [83] | ~13-fold (4000 nM) | >300-fold selectivity over a small panel of representative tyr/ser-thr kinases | Good oral bio-availability | Arthritis [84] Colitis [85] Cardiac graft rejection [86] T-ALL [87] Glioma [50] Prostate cancer [88] |
| Withaferin A | Cys179-binding | [89,90,91,92] | N/A | Broad spectrum inhibitor [93]Vimentin, HSP90, β-tubulin, Desmin, Annexin-A2, Notch-1, STAT1/3 | Poor oral bioavailability | N/A |
| BOT-64 | Ser-177/181 binding | 1000–3000 [94] | N/A | N/A | Administered intra-peritoneally | N/A |
| Ainsliadimer A | Cysteine-46 binding | 30 [95] | N/A | No significant activity against 340 human kinases at 200 nM | Administered intravenously | N/A |
* Value as reported in the reference, from activity or binding assay, not corrected for ATP concentration.