Z-Gly-Pro-Phe-Leu-CHO (Z-GPFL-CHO) is a tetrapeptide aldehyde that acts as a highly selective and potent proteasomal inhibitor (Ki = 1.5 µM for branched chain amino acid preferring, 2.3 µM for small neutral amino acid preferring, and 40.5 µM for chymotrypsin-like activities; IC50 = 3.1 µM for peptidyl-glutamyl peptide hydrolyzing activity)[1].
Ixazomib citrate (MLN9708) is a reversible inhibitor of the chymotrypsin-like proteolytic β5 site of the 20S proteasome with an IC50 of 3.4 nM and a Ki of 0.93 nM.
Gabexate Mesylate is a Factor X inhibitor; serine protease inhibitor .Target: Factor XGabexate mesylate is a non-antigenic synthetic inhibitor of trypsin-like serine proteinases that is therapeutically used in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for hemodialysis. Values of the inhibition constant (K(i)) for gabexate mesylate binding to human and bovine tryptase were 3.4 x 10(-9) M and 1.8 x 10(-7) M (at pH 7.4 and 37.0 degrees ), respectively. Gabexate mesylate inhibited the fibrinogenolytic activity of human tryptase [1]. Gabexate Mesylate decreased the TNFalpha production of LPS-stimulated monocytes as shown by the inhibition of mRNA expression and increased the IL-10 production of LPS-stimulated monocytes. Gabexate Mesylate also suppressed the NFkappaB activity of LPS-stimulated monocytes. Inhibitory effect of Gabexate Mesylate on the TNFalpha production of activated human monocytes is mediated by the suppression of NFkappaB activation [2]. Gabexate mesylate inhibits competitively constitutive and inducible NO synthase (cNOS and iNOS, respectively), with Kivalues of 1.0×10?4M and 5.0×10?3M, respectively, at pH 7.4 and 37.0°C. gabexate mesylate increases iNOS mRNA expression in rat C6 glioma cells, as induced byE. colilipopolysaccharide plus interferon-γ. Gabexate mesylate inhibits dose-dependently nitrite production (i.e. NO release) in rat C6 glioma cells, as induced byE. colilipopolysaccharide plus interferon-γ [3].
Rpn11-IN-1 is a potent and selective inhibitor of proteasome subunit Rpn11 with an IC50 of 390 nM.
Z-Leu-Leu-Glu-AMC is a substrate peptide, and can be used for determination of postacidic-like hydrolysing activity of 20S proteasome[1]
5-Amino-8-hydroxyquinoline (5A8HQ), a potential anticancer candidate, has promising proteasome inhibitory activity.
Calpain-2-IN-1 is a calpain-2 selective inhibitor that enhances learning & memory by prolonging ERK activation.
BC-23 (NSC 45382) is a proteasome inhibitor. BC-23 exhibits good inhibition of CT-L activity of the proteasome and is selective for malignant over normal cells[1][2].
ALLM (Calpain inhibitor II) is a potent inhibitor of calpain and cathepsin proteases. ALLM inhibits neuronal cell death and improves chronic neurological function after spinal cord injury (SCI)[1][2].
PI-1840 is a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nM) over trypsin-like and peptidylglutamyl peptide hydrolyzing (IC50 values >100 μM) activities of the proteasome. IC50 value: 27 nM(CT-L activities of the proteasome) [1]Target: CT-L inhibitorin vitro: PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Mass spectrometry and dialysis studies demonstrate that PI-1840 is a noncovalent and rapidly reversible CT-L inhibitor. In intact cancer cells, PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax, and IκB-α, inhibits survival pathways and viability, and induces apoptosis. Furthermore, PI-1840 sensitizes human cancer cells to the mdm2/p53 disruptor, nutlin, and to the pan-Bcl-2 antagonist BH3-M6 [1].in vivo: PI-1840 but not bortezomib suppresses the growth in nude mice of human breast tumor xenografts [1].
Z-Leu-Tyr-Chloromethylketone is a calpain inhibitor[1].
Z-LLF-CHO (Z-Leu-Leu-Phe-CHO) is a potent inhibitor of the chymotrypsin-like activity of the pituitary multicatalytic proteinase complex (Ki = 460 nM). Z-LLF-CHO is also a NF-κB nuclear translocation inhibitor[1][2].
A potent, specific immunoproteasome LMP7 subunit inhibitor with IC50 of 25 nM, >100-fold selectivity over β5c, β1i, β1c, β2i and β2c subunits (IC50>3 uM); shows weak activity toward LMP2 and no detectable activity toward β1, β2, or MECL1.
(1S,2R)-Alicapistat ((1S,2R)-ABT-957) is an orally active selective inhibitor of human calpains 1 and 2 for the potential application of Alzheimer's disease (AD)[1]. (1S,2R)-Alicapistat mitigates the metabolic liability of carbonyl reduction and inhibits calpain 1 with an IC50 value of 395 nM[2].
Proteasome inhibitor IX (PS-IX; AM114) is a Chalcone derivative and a chymotrypsin-like activity of the 20S proteasome inhibitor with an IC50 value of ~1 μM. Proteasome inhibitor IX exhibits HCT116 p53+/+ cells growth inhibitory activity with an IC50 value of 1.49 μM. Proteasome inhibitor IX has potent anticancer activity[1][2].
Lactacystin, an antibiotic Streptomyces spp. metabolite, is a potent and selective proteasome inhibitor with an IC50 of 4.8 μM for 20S proteasome. Lactacystin also inhibits the lysosomal enzyme cathepsin A[1]. Lactacystin inhibits cell growth and induces neurite outgrowth[2].
Isovalerylcarnitine chloride, a product of the catabolism of L-leucine, is a potent activator of the Ca2+-dependent proteinase (calpain) of human neutrophils[1].
Proteasome-IN-5 (compound 5) is a proteasome inhibitor[1].
PR-39, a natural proline- and arginine-rich antibacterial peptide, is a noncompetitive, reversible and allosteric proteasome inhibitor. PR-39 reversibly binds to the α7 subunit of the proteasome and blocks degradation of NF-κB inhibitor IκBα by the ubiquitin-proteasome pathway. PR-39 stimulates angiogenesis, inhibits inflammatory responses and significant reduces myocardial infarct size in mice[1][2].
20S Proteasome-IN-2 is a human 20S proteasome inhibitor. 20S Proteasome-IN-2 shows high selectivity to its β5 subunit with the IC50 of 0.18 μM. 20S Proteasome-IN-2 displays anti-proliferative effect in vitro and in vivo, and arrests cell cycle at G2/M[1].
Carfilzomib is an irreversible proteasome inhibitor with an IC50 of 5 nM in ANBL-6 and RPMI 8226 cells.
LU-002i is a subunit-selective human proteasome β2c and β2i inhibitor with an IC50 value of 220 nM for β2i[1].
Delanzomib(CEP-18770) is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity.IC50 Value: 3.8 nM [1]Target: proteasomein vitro: CEP-18770 and bortezomib showed comparable potency against chymotrypsin-like proteasome activity, cellular inhibitory activity (IC50) values of 3.8 (± 1.0) nM and 3.8 (± 0.4) nM, respectively, CEP-18770 had a 2- to 11-fold lower cytotoxic potency compared with bortezomib against solid tumor cell lines, comparable potency against 2 hematologic tumor cell lines, and a similar spectrum of antiproliferative activity with IC50 values for both compounds of less than 35 nM [1].in vivo: in MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone [2]. Age matched MRL/lpr or NZBWF1 mice with established SLE or LN, respectively, were treated with delanzomib either 3 mg/kg once or twice weekly intravenously or orally at 10 mg/kg [3]. Toxicity: CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule [4].Clinical trial: CEP-18770 in Combination With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma. Phase1/2
Alicapistat (ABT-957) is an orally active selective inhibitor of human calpains 1 and 2 for the potential use in the treatment of Alzheimer's disease (AD).
(1S,2S)-Bortezomib is an enantiomer of Bortezomib. Bortezomib is a cell-permeable, reversible, and selective proteasome inhibitor, and potently inhibits 20S proteasome (Ki of 0.6 nM) by targeting a threonine residue. Bortezomib disrupts the cell cycle, induces apoptosis, and inhibits NF-κB. Bortezomib is an anti-cancer agent and the first therapeutic proteasome inhibitor to be used in humans[1][2][3].
cysteine protease inhibitor of calpain that rapidly penetrates the blood-brain barrier following systemic administration[1][2]. MDL-28170 also block γ-secretase[4].
A-933548 is a potent Calpain inhibitor. A-933548 features enhanced selectivity versus related cysteine protease cathepsins, favorable microsomal stability, and efficacy in cellular assays.
KZR-616 maleate, a first-in-class immunoproteasome inhibitor, selectively targets the LMP7 (IC50: 39/57 nM=hLMP7/mLMP7) and LMP2 (IC50: 131/179 nM=hLMP7/mLMP7) subunits of the immunoproteasome. KZR-616 maleate has the potential for the research of multiple autoimmune diseases[1][2].
MeOSuc-Gly-Leu-Phe-AMC is a peptide substrate of proteasomal[1].
Calpain Inhibitor-1 (compound 36) is a potent and selective cysteine protease calpain 1 (Cal1) inhibitor (IC50=100 nM; Ki=2.89 μM)[1].