Ixazomib Citrate (MLN9708) Analogue

Pan Proteasome Inhibitor

Ixazomib (MLN2238) : β5 site, IC50=3.4 nM; β1 site, IC50=31 nM; β2 site, IC50=3500 nM.

FDA-approved Proteasome Inhibitor

Carfilzomib (PR-171) : Approved by FDA for multiple myeloma.

Newest Proteasome Inhibitor

Oprozomib (ONX 0912) : Orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM.

Classic Proteasome Inhibitor

ONX-0914 (PR-957) : Selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome.

VR23 ^New

VR23 is a potent proteasome inhibitor with IC50 of 1 nM, 50-100 nM, and 3 μM for trypsin-like proteasomes, chymotrypsin-like proteasomes, and caspase-like proteasomes, respectively.

Calpeptin ^New

Calpeptin is a potent, cell-permeable calpain inhibitor with ID50 of 52 nM, 34 nM, 138 nM, and 40 nM for Calpain I (porcine erythrocytes), Calpain II (porcine kidney), Papainb, and Calpain I (human platelets), respectively. Calpeptin attenuates apoptosis and intracellular inflammatory changes in muscle cells.

Marimastat (BB-2516) ^New

Marimastat (BB-2516, TA2516) is a broad spectrum matrix metalloprotease (MMP) inhibitor for MMP-9, MMP-1, MMP-2, MMP-14 and MMP-7 with IC50 of 3 nM, 5 nM, 6 nM, 9 nM and 13 nM, respectively. Phase 3.

MG-132

MG132 (Z-Leu-Leu-Leu-al) is a potent cell-permeable proteasome and calpain inhibitor with IC50s of 0.1 μM and 1.2 μM for the inhibition of proteasome and calpain, respectively. MG132 activates autophagy and induces apoptosis in tumor cells.

Bortezomib (PS-341)

Bortezomib (PS-341, Velcade, LDP-341, MLM341, NSC 681239) is a potent 20S proteasome inhibitor with K_i of 0.6 nM. It exhibits favorable selectivity towards tumor cells over normal cells. Bortezomib (PS-341) inhibits NF-κB and induces ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy in ovarian cancer and other solid tumors.

Carfilzomib (PR-171)

Carfilzomib (PR-171) is an irreversible proteasome inhibitor with IC50 of <5 nM in ANBL-6 cells, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities. Carfilzomib activates prosurvival autophagy and induces cell apoptosis.

Ixazomib (MLN2238)

Ixazomib (MLN2238) inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and K_i of 3.4 nM and 0.93 nM in cell-free assays, respectively, also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites, with IC50 of 31 and 3500 nM. Ixazomib (MLN2238) induces autophagy. Phase 3.

Features:A first-in-class proteasome inhibitor that has improved pharmacokinetics (PK), pharmacodynamics(PD), and antitumor activity in preclinical studies.

ONX-0914 (PR-957)

ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.

Features:The first highly selective, small molecule inhibitor of the immunoproteasome. Potential use in cancer and autoimmune diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, and lupus).

Celastrol (NSC 70931)

Celastrol (NSC 70931, Tripterine) is a potent proteasome inhibitor for the chymotrypsin-like activity of a purified 20S proteasome with IC50 of 2.5 μM. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway. Celastrol inhibits dopaminergic neuronal death of Parkinson's disease through activating mitophagy.

Features:A potent antioxidant and anti-inflammatory drug.

Oprozomib (ONX 0912)

Oprozomib (ONX 0912, PR-047) is an orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM. Phase 1/2.