Table 4.
Inhibitors of immunoproteasome, E3 ligases, 19S proteasome and DUBs.
| Target | Inhibitor | Structural Class | Inhibition Property | Major biological effects | Development Stage |
|---|---|---|---|---|---|
| Immunoproteasome | IPSI-001 | Aldehyde | β1i> β5i> 20S | Overcome BTZ resistance | Preclinical |
| Immunoproteasome | ONX-0914 PR-924 |
Epoxyketone | β5i> β5, β1i | Overcome BTZ resistance | Preclinical |
| Ubiquitin E3 ligase (HDM2) |
Nutlin-3 | cis-Imidazoline | p53 binding pocket on HDM2 |
Accumulation of p53 and increased expression of p53 targets |
Prototype |
| Ubiquitin E3 ligase (HDM2) |
RO5045337 RO5503781 |
cis-Imidazoline | p53 binding pocket on HDM2 |
Accumulation of p53 and increased expression of p53 targets |
Phase I |
| Ubiquitin E3 ligase (IAP) |
LCL161 | Smac peptide mimetic | Binding and inhibiting IAP |
IAP degradation | Phase I-II |
| Ubiquitin E3 ligase (IAP) |
AEG 35156 | IAP antisense | Binding and inhibiting IAP |
IAP degradation | Phase I-II |
| Ubiquitin E3 ligase (Cereblon) |
Lenalidomide Pomalidomide |
Thalidomide analogs | Cereblon | Immunomodulatory and anti- tumorigenic effects |
Approved |
| 19S proteasome (proteasome recognition site) |
Ubistatins | Quinolines | Ub-Ub interface | Blocking the binding of ubiquitinated substrates to the proteasome |
Pre-clinical |
| 19S proteasome- associated DUBs |
b-AP15 | bis-Nitrobenzylidene- piperidinone |
USP14, UCH-L5 | Blocking cleavage of K48-linked ubiquitin chains and accumulating polyubiquitinated proteins |
Pre-clinical |
| DUBs | P5091 P22077 |
Thiophene | USP7 | Deubiquitinating p53 and HDM2; overcoming BTZ resistance |
Pre-clinical |
| DUBs | WP-1130 | Tyrphostin | Multiple DUBs (USP9x, USP5, USP14, UCH-L5) |
Regulating survival protein stability and 26S proteasome function; synergetic effect with BTZ |
Pre-clinical |