Table 1.
Small-molecule inhibitors of the proteasome, E1 activating enzymes, and E2 conjugating enzymes.
| Compound Name | UPS Target | Mode of Action | Current Clinical Stage | Cancer Models Targeted in Preclinical Studies | Targeted Cancer Types in Clinical Trials | Clinical Trial Results |
|---|---|---|---|---|---|---|
| Proteasome Inhibitors | ||||||
| Bortezomib | Proteasome (20S particle) | Reversibly binds active sites of 20S proteasome | FDA approved (Phase 4) | MM, lymphocytic leukemia cells, oral squamous carcinoma cells, and more [32] | MM, AML, colorectal cancer, head and neck cancer, mantle cell lymphoma, and more | [59,60,61] |
| Carfilzomib | Proteasome (20S particle) | Irreversibly binds active sites of 20S proteasome | FDA approved (Phase 4) | Hematologic tumors [37] | MM, lymphoma, thyroid cancer, lung cancer, kidney cancer, and more | [36,62,63,64] |
| Oprozomib | Proteasome (20S particle) | Irreversibly binds active sites of 20S proteasome | Phase 1b/2 | MM [65] | Solid tumors, hepatocellular carcinoma, MM, waldenstrom macroglobulinemia, and more | [66] |
| Ixazomib | Proteasome (20S particle) | Inhibits chymotrypsin-like activity of 20S proteasome | FDA approved (Phase 4) | Solid and hematologic tumors [67], MM [68], B-cell, plasma cell malignancies [69] | MM, relapsed/refractory MM, AML, Hodgkin and T-cell lymphoma, breast cancer, and more | [70,71] |
| IU1, IU1-47, 1B10, IU1-248 | Proteasome (19S particle) | Inhibit USP14 (proteasome-associated DUB) via steric site | Preclinical | N/A | N/A | N/A |
| b-AP15 | Proteasome (19S particle) | Targets UCHL5 and USP14 (proteasome-associated DUBs) | Preclinical | Solid tumors, MM [40,72,73,74] | N/A | N/A |
| VLX1570 | Proteasome (19S particle) | Analog of b-AP15, also targets UCHL5 and USP14 | Preclinical (Phase 1/2 terminated) | MM [42] | MM | N/A |
| WP1130 | Proteasome (19S particle) | Inhibits USP9X, UCHL, and USP14 | Preclinical | Chronic myelogenous leukemia (CML), melanoma, glioblastoma, myeproliferative disorders [44,75,76], MCL [77], AML [78] | N/A | N/A |
| RA-9 | Proteasome (19S particle) | Inhibits proteasome-associated DUBs | Preclinical | Ovarian cancer [43] | N/A | N/A |
| RA190 | Proteasome (19S particle) | Inhibits RNP13 and inactivates Uch37 | Preclinical | MM, ovarian cancer [45] | N/A | N/A |
| Capzimin, 8TQ | Proteasome (19S particle) | Specifically target RPN11 | Preclinical | Leukemia, NSCLC, breast cancer [79] | N/A | N/A |
| Thiolutin, SOP11 | Proteasome (19S particle) | Targets RPN11 and other JAMM-family DUBs | Preclinical | Colon cancer, bortezomib-resistant RPE cells [80] | N/A | N/A |
| E1 inhibitors | ||||||
| PYR-41 | UBA1 | Irreversibly binds active site cysteine of UBA1 | Preclinical | N/A | N/A | N/A |
| MLN4942 (Pevonedistat) | NAE | Binds NEDD8, prevents CRL neddylation to inhibit activity | Phase 3 | Colon cancer, lung cancer, myeloma, lymphoma [81,82,83] |
AML, MM, lymphoma, melanoma, lung cancer, PCM, and more | [84,85,86,87] |
| E2 inhibitors | ||||||
| CC0651 | hCdc34 | Binds allosteric pocket causing structural displacement | Preclinical | Prostate and colorectal cancer cell lines [88] | N/A | N/A |
| NSC697923 | Ubc-Uev1A | Impedes formation of Ubc13 and Ub thioester conjugate | Preclinical | Diffuse large B-cell lymphoma (DLBCL) [89] | N/A | N/A |