Table 1.
Fda-approved and investigational proteasomal inhibitors for the treatment of human disease.
| DISEASE | STRUCTURE | STATUS | ACTIVE SITE | DISEASE TARGET/ DISEASE MODEL | ||
|---|---|---|---|---|---|---|
| ONCOLOGY | ||||||
| Bortezomib (Orlowski and Kuhn, 2008; Dick and Fleming, 2010; Kisselev et al., 2012; Fricker, 2020) | Dipeptidyl boronate | FDA-Approval | β5>β1>>β2 | MM, MCL, DLBCL | ||
| RRMM (2003) | ||||||
| MM (2007) | ||||||
| Previously untreated MM (2008) | ||||||
| SC injection for all approved indications (2012) | ||||||
| MCL- with at least one prior tx (2007) | ||||||
| Carfilzomib (Kuhn et al., 2007; Huber and Groll, 2012; Herndon et al., 2013; Park et al., 2018; Jayaweera et al., 2021) | Tetrapeptide epoxyketone | FDA-Approval | β5>β1>β2 | MM | ||
| Advanced MM (2012) | ||||||
| Relapsed MM (2015) | ||||||
| RRMM (2016) | ||||||
| Ixazomib (Kumar et al., 2014; Al-Salama et al., 2017) | Dipeptidyl boronate, oral | FDA-Approval | β5>β1>>β2 | Oral agent, MM | ||
| RRMM (2015) | ||||||
| Marizomib (Huber and Groll, 2012; Park et al., 2018; Fricker, 2020) | β-lactone | FDA orphan status | β5>β2>β1 | MM, crosses BBB | ||
| (Salinosporamide A, NPI-0052) | MM (2013) | |||||
| Delanzomib (Huber and Groll, 2012; Park et al., 2018; Fricker, 2020) | C-terminal boronic acid peptide (phenylpyridine) | β5>β1>>β2 | MM | |||
| (CEP-18770) | ||||||
| ONX-0912 (Johnson et al., 2017; Schmidt et al., 2018; Xi et al., 2019) | Orphan status | β5>β1>>β2 | MM, WM | |||
| (Oprozomib, PR-047) | oral | NCT02072863 | ||||
| Lactacystin (Orlowski and Kuhn, 2008; Dick and Fleming, 2010; Kisselev et al., 2012; Fricker, 2020) | β-lactone | Pre-clinical | β5>β1>>β2 | Cancers, MM | ||
| TMC-95A, B, C, D (Koguchi et al., 2000) | Apiospora broth | Pre-clinical | β5>β1>>β2 | TMC-95A and diastereomers (B-D) exhibited cytoxicity against human HCT-116 colon | ||
| AUTOIMMUNE DISEASES | ||||||
| ONX-0914 (Kuhn et al., 2007; Huber and Groll, 2012; Herndon et al., 2013; Johnson et al., 2017; Park et al., 2018; Schmidt et al., 2018; Xi et al., 2019; Jayaweera et al., 2021) | Tripeptide Epoxyketone | Investigational | β5i>β1i>β2i | Experimental/murine autoimmune, rheumatoid arthritis, encephalomyelitis, inflammatory bowel disease, and GVHD models | ||
| (PR-957) | ||||||
| KZR-504 (Johnson et al., 2017; Xi et al., 2019) | Dipeptide Epoxyketone | Investigational | β1i>β5i>β2 | RA, SLE | ||
| KZR-616 (Johnson et al., 2017; Xi et al., 2019) | Tetrapeptide Epoxyketone | NCT03393013 | β5i>β1i>β2i | SLE with and without Lupus Nephritis | ||
| NCT04033926 | Polymyositis or Dermatomyositis | |||||
| NCT04039477 | Active Autoimmune Hemolytic Anemia or ITP | |||||
| TUBERCULOSIS | ||||||
| GL5 (Totaro et al., 2017) | Oxathiazole-2-one derivative | Pre-clinical | β5 | Mtb20S-selective Kills non-replicating Mtb under NO stress Selective suicide substrate inhibitor of Mtb 20S OG proteasomes Cyclocarbonylates active site Thr >1,000-fold more effective against Mtb than human proteasomes |
||
| HT1171 (Totaro et al., 2017) | Oxathiazole-2-one derivative | Pre-clinical | β5 | Mtb20S-selective Kills non-replicating Mtb under NO stress Selective suicide substrate inhibitor of Mtb 20S OG proteasomes Cyclocarbonylates the active site Thr >1,000-fold more effective against Mtb than human proteasomes |
||
| HT1171 (Totaro et al., 2017) | Oxathiazole-2-one derivative | Pre-clinical | β5 | Mtb20S-selective Kills non-replicating Mtb under NO stress Selective suicide substrate inhibitor of Mtb 20S OG proteasomes Cyclocarbonylates the active site Thr >1,000-fold more effective against Mtb than human proteasomes |
||
| Fellutamide B (Lin et al., 2010) | Lipopeptide aldehyde | Pre-clinical | β5 | Inhibits wild type (Mtb20SWT) and open-gate mutant (Mtb20SOG) Mtb proteasomes | ||
| Inhibits Mtb proteasome through one-step mechanism, inhibits hu20S proteasome through two-step mechanism | ||||||
| Syringolin (Totaro et al., 2017) | Natural products | Pre-clinical | β5 | Species selective, bioactive Mtb inhibitors | ||
| Analogues A/B | Macrocyclic lactam attached to an exocyclic dipeptide urea | 74-fold > selectivity for Mtb > hu20S proteasomes | ||||
| Cell-permeable, covalent, irreversible | ||||||
| DPLG2 (Lin et al., 2013) | Phenylimidazole-based, | Pre-clinical | β5 | 4,667-fold selective for Mtb proteasomes over human c20S and 3,647-fold over i20S proteasomes | ||
| N, C-Capped dipeptide | Cell-permeable, kill non-replicating Mtb under nitrosative stress | |||||
| B6 (Zhan et al., 2019) | Phenylimidazole peptidomimetic |
Pre-clinical | β5 | >12,500-fold selective for Mtb proteasomes than human c20S and i20S proteasomes | ||
| TDI5575 (Zhang and Lin, 2021) | Macrocyclic | Translational | β5ic>β5c> | Kills non-replicating Mtb under NO stress | ||
| Peptides | β2i, β2c, β1i, β1c | Induces accumulation of pupylated proteins | ||||
| Stable in plasma | ||||||
| MALARIA | ||||||
| Artemisinins (Bridgford et al., 2018) | Natural bioactive sesquiterpene lactone containing an unusual endoperoxide 1,2,4-trioxane ring |
First-line treatment for uncomplicated P. falciparum malaria |
Upregulation of the UPR Inhibits proteasome function Fast-acting against intraerythrocytic asexual blood-stage malaria Short half-life in vivo |
|||
| Artesunate (Dondorp et al., 2010) | Semi-synthetic Lactol derivative |
FDA-approved (IV) for severe malaria in adults and children |
||||
| Artemether (Esu et al., 2019) | Semi-synthetic Lactol derivative |
β5>β1>>β2 | Multi-pronged assault on protein homeostasis Activates ER stress, toxic accumulation of poly-Ub- proteins, kills parasites |
|||
| WLW-vs (Stokes et al., 2019) | Peptide vinyl sulfones Irreversible |
Pre-clinical | β2-selective | Plasmodium-selective, attenuate parasite growth in vivo in murine models | ||
| TDI-8304 (Zhan et al., 2021) | Macrocyclic peptide | Pre-clinical | β5 | Species-selective Reduces parasitemia in humanized P. falciparum- infected mouse |
||
| PW28 (Tschan et al., 2013) | Peptido sulfonyl fluoride | Pre-clinical | Malaria | |||
| Carmaphycin B | (Cbz-LLLL-VF) Natural product |
|||||
| analog 18 (LaMonte et al., 2017) | N-hexanoyl tripeptide, α,β-epoxyketone |
Pre-clinical | β5 | Inhibit β5 activity, blood-stage and gametocidal antimalarial activity | ||
| OZ439 (Charman et al., 2011) | Synthetic ozonide | Phase 2 trial | Good safety profile that clears parasitemia rapidly in both P. falciparum and P. vivax malaria | |||
| (Artefenomel) | Artemisinin pharmacophore | |||||
| MPI-5 (Xie et al., 2021) | Amino-amide boronate | Pre-clinical | Selective, potent anti-malarial activity across the parasite lifecycle, fast-acting, species selective over human proteasome, high selectivity for Pf cultures | |||
| Oral availability, efficacy in SCID mouse model | ||||||
| MPI-13 (Xie et al., 2021) | Amino-amide boronate | Pre-clinical | Selective, potent anti-malarial activity across the parasite lifecycle, fast-acting, species selective over human proteasome, high selectivity for Pf cultures | |||
| Oral availability, efficacy in SCID mouse model | ||||||
| PROTOZOA | ||||||
| GNF5343 (Khare et al., 2016) | Azabenzoxazole | Investigational | β5 | Inhibits kinetoplastid proteasome and growth | ||
| Potent anti-L. donovani and anti-T. brucei activity for the treatment of Leishmania, Chagas disease, and Sleeping sickness | ||||||
| GNF6702 (101) | Azabenzoxazole | Investigational | β5 | Optimization of GNF5343. Reduced risk of toxicity, improved selectivity over mammalian cell growth inhibition, low clearance, acceptable bioavailability and a 400-fold increase in potency against intra-macrophage L. donovani compared with GNF5343 | ||