Table 1 PIs utilized in hematologic malignancies
PI | Binding type | Subunit Inhibition | Descriptions (Target residue/ Administration Route/ History of FDA) | Clinical Trials | |
|---|---|---|---|---|---|
BTZ (Velcade) (PS-341) [88] | Reversible [89] | ß5 and LMP7 [88] Chymotrypsin-like activity ß5 and β1-subunit in immunoproteasomes as caspase-like activity at lower affinity [90, 91]. | Subcutaneous and Intravenous (IV) [92] First synthesized in 1995 [6] FDA: May 2003 for relapsed/refractory MM [93] 2006 for MCL [94] | NCT01248923 | MM, PCL |
NCT00006362 | Leukemia, Lymphoma, MM, PCL | ||||
NCT00303797 | Refractory CLL, Refractory MM, Stage III MM, Stage IV CLL | ||||
NCT00295932 | Leukemia, Lymphoma | ||||
NCT00440765/ NCT00440479 | MM, Hematological Neoplasms | ||||
NCT00038571 | R/R B cell lymphoma | ||||
NCT00477412/ NCT00633594/ NCT01504776 | MCL | ||||
NCT00901147 | Recurrent/ Refractory Peripheral T-cell Lymphoma, NK/T-cell Lymphoma | ||||
Carfilzomib (Kyprolis) (PR-171) [88] | Irreversible [88] | ß5 and LMP7 [88] both ß5 and ß2 [90] β5, LMP2 and MECL1 subunits of the immunoproteasome [88] Proteasome subunit ß5 [95] ß8, ß1, ß9, ß2, ß10: [96] | Threonine residue [88] Intravenous [90] FDA: July 2012 [97] | NCT01658904/ NCT04065789 | MM, PCL |
NCT00150462 | WM, NHL, HD, MM | ||||
NCT01470196 | WM | ||||
NCT01276717 | Relapsed / Recurrent/ Refractory Lymphoma | ||||
NCT01775553/ NCT03029234/ NCT04811508/ NCT00603447 | Relapse/ Recurrent/ Refractory MM | ||||
NCT01949532 | Relapse MM, End-stage renal disease | ||||
NCT01949545 | Solid Tumors, Hematologic Malignancies, Hepatic Impairment | ||||
NCT02145403 | Hematologic Malignancies, Relapse GVHD | ||||
NCT02142530 | NHL, DLBL, FL, Peripheral T-cell Lymphoma | ||||
NCT00721734 | MM, Renal Insufficiency | ||||
NCT01926665 | Lymphoma | ||||
NCT01336920 | Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma | ||||
NCT00884312 | MM, Solid Tumors | ||||
NCT01212380 | B- CLL, Hematopoietic/Lymphoid Cancer, PLL, Recurrent SLL, Refractory CLL | ||||
NCT01137747 | Relapsed AML or ALL | ||||
NCT02095834/ NCT01903811 | Recurrent/ Refractory Plasma Cell Myeloma | ||||
NCT02491359 | Chronic GVHD | ||||
NCT02187133 | Lymphoma,NHL | ||||
NCT01204164 | AML, ALL, Blast Crisis of CML,MDS, MM | ||||
NCT02551718 | Recurrent Refractory Acute Leukemia of Ambiguous Lineage, Recurrent Refractory ALL, Recurrent Refractory AML | ||||
Ixazomib citrate (Ninlaro) (MLN9708) (MLN 2238) [88] | Reversible [89] | ß5 and LMP7 [88] β5 site, at higher concentrations, also seems to inhibit the proteolytic β1 and β2 subunits: [90, 98] | Threonine residue [88] IV, Oral [100] FDA: November 2015 [101] | NCT02169791 | Acute Leukemia, Chronic Leukemia, MDS, Lymphomas, MM |
NCT02070458 | Recurrent/ Refractory Adult AML | ||||
NCT00893464 | Lymphoma | ||||
NCT03323151 | Active, not recruiting: Relapsed/Refractory MCL | ||||
NCT04079738 | Active, not recruiting: Relapsed/Refractory AML, Adult AML | ||||
NCT03082677 | to Prevent Recurrent or Late Acute and Chronic GVHD 1-year After Allogeneic HSCT in Patients With Hematologic Malignancies | ||||
NCT01939899 | Relapsed and/or Refractory FL | ||||
NCT01830816 | MM, Advanced Solid Tumors | ||||
NCT01953783 | Advanced Solid Tumors, Lymphoma | ||||
NCT02057640 | MM, Kahler Disease, Plasma-Cell Myeloma, Myelomatosis | ||||
NCT02250300 | Allogeneic HSCT | ||||
NCT02513498 | Chronic GVHD | ||||
NCT02504359 | Relapsed High-Risk MM, PCL, Recurrent PCL | ||||
NCT01912222 | Advanced Solid Tumors, Hematologic Malignancies | ||||
NCT02400437 | WM | ||||
NCT02158975 | Relapsed/Refractory Cutaneous and Peripheral T-cell Lymphomas | ||||
LMP7 [88] | Threonine residue [88] Oral [100] Orphan drug by the U.S. FDA for the treatment of rare type of blood cancer (Waldenstrom’s macroglobulinemia) https://myelomaresearchnews.com) analog of carfilzomib | NCT02072863 | MM | ||
NCT02939183 | Active, not recruiting: R/R MM | ||||
Marizomib (natural product, named salinosporamide A) (NPI-0052) (MRZ) [97, 100] | Threonine residue [100] IV (Oral and Subcutaneous efficacy in vivo) [100] | NCT00629473/ NCT00461045 | MM | ||
NCT02103335 | R/R MM | ||||
NCT00667082 | Non-Small Cell Lung Cancer, Pancreatic Cancer, Melanoma, Lymphoma, MM | ||||
NCT00396864 | Cancer, Lymphomas | ||||
Delanzomib (CEP-18770) (CIP 18770) (CT 47098) (NPH-007098): [97] | Chymotrypsin-like and Caspase-like activities of the proteasome (β5 and β1) [85, 90] | Threonine residue [100] IV (Oral efficacy in vivo) [100] | NCT00572637 | Solid Tumors, NHL | |
NCT01023880 | Phase I/II Study for Relapsed Refractory MM [102] | ||||
(KZR-616) a derivative of ONX-0914: [88] | LMP2 and LMP7 [88] | Threonine residue [103] | NCT03393013 | Lupus Nephritis Systemic Lupus Erythematosus | |
M3258: [104] | Reversible [89] | Threonine residue [105] Oral (animal model) [89] | NCT04075721 | MM | |
– | Inhibits > 95% of LMP7 (ß5i) and 60–80% of LMP2 (ß1i) activity of the immunoproteasome: [104] | - - - - - - | – | – | |
LU-102 [104] | – | MECL1 and ß2c [104] | – | – | – |