UbcH5c inhibitor DHPO is a small molecule UbcH5c inhibitor, directly targets UbcH5c with KD of 37.5 uM.DHPO effectively engaged by the UbcH5c protein in both Panc1 and SW1990 cells.DHPO exerts significant growth inhibition in pancreatic cancer cells in vitro (IC50=2.3-8.5 uM), prevents the migration and invasion of both Panc1 and SW1990 cells.DHPO inhibits pancreatic cancer cell growth and metastasis by inhibiting the NF-κB pathway.DHPO suppresses orthotopic pancreatic tumor growth in vivo, without causing significant host toxicity.DHPO prevents metastasis of pancreatic cancer in vivo.

TG-6304 (TG6304) is a first-in-class, potent, highly selective, cell-permeable DCN3 inhibitor with Ki of 35 nM, does not bind to DCN1 at 30 uM.TC-6304 engages DCN3 in cells in a dose-dependent manner but does not affect the neddylation of any of the cullins.TC-6304 effectively enhances the thermal stability of cellular DCN3 protein in a dose-dependent manner and has no significant effect on the thermal stability of cellular DCN1 protein (10-1000 nM).

SU086 is an inhibitor of HSP90, binds to HSP90-alpha and HSP90-beta isoforms, decreases HSP90 protein levels in prostate cancer cells.SU086 is a potent inhibitor of prostate cancer cell growth, migration, and invasion in vitro, significantly inhibited growth of AR-positive CRPC cell lines (C4-2), AR-negative (DU145 and PC-3) CRPC cells, and CRPC cells with expression of AR and AR splice variant, AR-V7 (22Rv1) (IC50 <10 uM).SU086 inhibits prostate cancer growth in preclinical models of prostate cancer in vivo.SU086 strongly enhances the anti-tumor activity of standard of care second-generation anti-androgens enzalutamide and abiraterone and inhibits prostate cancer cell growth in vitro and tumor growth in vivo.

SEW84 (SEW04784) is a first-in-class, specific inhibitor of the Aha1-stimulated Hsp90 (ASH) ATPase activity (IC50=0.3 uM) without inhibiting basal Hsp90 ATPase; SEW84 binds to the C-terminal domain of Aha1 (Kd=1.7 uM) to weaken its asymmetric binding to Hsp90. SEW84 inhibited the GR- and AR-dependent luciferase expression with IC50 of 1.3 uM and 0.7 uM respectively. SEW84 blocks Aha1-dependent Hsp90 chaperoning activities, including the in vitro and in vivo refolding of firefly luciferase, and the transcriptional activity of the androgen receptor in cell-based models of prostate cancer. SEW84 promotes the clearance of phosphorylated tau in cellular and tissue models of neurodegenerative tauopathy.

S1g-2 (Hsp70-Bim inhibitor S1g-2) is a selective inhibitor to block interactions of Hsp70-Bim with IC50 of 0.4 uM in FPA assays, > 40-fold selectivity to target Hsp70-Bim over Bcl-2-Bim. S1g-2 induces cell-type-specific apoptosis in CML cells through selectively disrupting the Hsp70-Bim PPI. S1g-2 progressively enhanced lethality along with the increase in BCR-ABL-independent TKI resistance in the K562 cell lines. S1g-2 is more effective in primary samples from BCR-ABL-independent TKI-resistant patients than those from TKI-sensitive patients.

MyoMed-946 is a small moelcule that inhibits MuRF1 (TRIM63) activity and MuRF1/MuRF2 expression; MyoMed-946 inhibits MuRF1 expression/activity in vivo and is able to attenuate skeletal muscle atrophy and dysfunction in mice treated with monocrotaline to induce right ventricular hypertrophy and subsequent cardiac cachexia. MyoMed-946 attenuates skeletal muscle strength loss in mouse model for type 2 diabetes mellitus (T2DM), with no significant effects on serum glucose. MyoMed-946 attenuates induction of MuRF1 in tumor stressed muscles. MyoMed-946 also rescues citrate synthase and complex-1 activities in tumor-stressed muscles. MuRF1 (muscle-specific RING finger protein-1) is a muscle-specific ubiquitin ligase that regulates muscle catabolism during chronic wasting states, both MuRF1 and MuRF2 participate in glucose and, also, in lipid regulation.

MT16-205 (MT 16-205) is a potent, selective, covalent UCHL1 inhibitor with IC50 of 600 nM, no inhibition agianst UCHL3 (IC50>10 uM).MT16-205 inhibited both UCHL1 and the structurally unrelated DUB USP30 with similar potency.MT16-205 displayed cell proliferation cytotoxicity in human embryonic kidney cells (HEK293) with IC50 of 350 nM, MT16-205 effectively engaged UCHL1 in cells with IC50 of 830 nM.

MT16-001 is a selective, covalent inhibitor of deubiquitinating enzyme UCHL1 with IC50 of 580 nM, no inhibitory effect against UCHL3 (IC50>30 uM).MT16-001 inhibits structurally unrelated DUB USP30 with similar potency.MT16-001 showed cytotoxicity in human embryonic kidney cells (HEK293) with EC50 of 730 nM, effectively engaged UCHL1 in cells with EC50 of 550 nM.MT16-001 showed excellent selectivity for UCHL1 across the UCH family: UCHL1, UCHL3, UCHL5 and BAP1.

KUNB 31 is a potent, isoform-selective Hsp90β inhibitor with Kd of 0.18 uM, displays 50-fold selectivity over Hsp90α and Grp94; exhibits anti-proliferative activity against NCI H23, UC3, and HT-29 cancer cell lines with IC50 of 6.74 µM, 3.01 µM, and 3.72 µM, respectively; specificly induces the degradation of Hsp90β-dependent client proteins (EGFR, HER2, CDK4, CDK6, CXCR4 etc.) in cells.

KH-4-43 is a small moelcule E3 CRL4 inhibitor and exhibits antitumor potential, directly and selectively binds to the purified E3 ROC1-CUL4A CTD complex with Kd of 83 nM.KH-4-43 weakly binds to the purified, highly related E3 ROC1-CUL1 CTD complex with Kd of 9.4 uM, >100-fold less potent than ROC1-CUL4A CTD, showed little effect on Ub thiol ester formation with E1/E2 Cdc34.KH-4-43 inhibited the ubiquitination of CK1α by CRL4CRBN in vitro. Treatment of cells with KH-4-43 caused accumulation of the E3 CRL4 substrate CDT1.KH-4-43 inhibited cell viability against a panel of tumor lines, NB-4, MV4-11, OVCAR-3, and CAPAN-2 cell with IC50 of 1.8, 3.0, 3.9, and 4.8 uM, respectively.KH-4-43 suppress the growth of human tumor xenografts in mice.

Hsp90α-IN-12h is the first Hsp90α-selective inhibitor with IC50 of 460 nM, exhibit 48-fold selectivity versus other Hsp90 isoforms.In NCI-H522 cells, Hsp90a-dependent substrates are readily degraded in the presence of Hsp90a-selective inhibitor.

Hsp90 inhibitor 5b is a first-in-class, small molecule inhibitor of the C-terminal (CTD) Hsp90 dimerization with KD of 3.42 uM, IC50 of 1.3 uM against leukemia cell line K562.Hsp90 inhibitor 5b inhibits Hsp90 chaperone function, does not show any interaction with the NTD of Hsp90.Hsp90 inhibitor 5b down-regulated the phospho-BCR-ABL1 and total-BCR-ABL1 levels, as well as the related downstream signaling pathways, additionally reduced the expression of client proteins associated with Hsp90 chaperone activity, involving Akt, Stat5, and c-Myc.Hsp90 inhibitor 5b inhibited leukemic cell lines (K562, KCL22 and HL60) proliferation and induced apoptosis in a caspase 3/7 enzyme-dependent assay.Hsp90 inhibitor 5b is effective against resistant leukemia cells and in the zebrafish xenotransplantation model.

HS-131 is an imaging probe of Hsp90 activity by linking it to a near-infrared (nIR) dye, HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human breast cancers in vitro and in murine models.

GSK145A is a small molecule inhibitor of SUMO-conjugating enzyme E2 with IC50 of 12.5 uM, GSK145A is competitive with the sumoylation of the TRPS1 peptide substrates.

Gamitrinib is a small molecule mitochondrial Hsp90 inhibitor, selectively targets Hsp90 network in tumor mitochondria; Gamitrinibs were shown to accumulate in the mitochondria of human tumor cell lines and to inhibit Hsp90 activity by acting as ATPase antagonists. Unlike Hsp90 antagonists not targeted to mitochondria, Gamitrinibs exhibited a "mitochondriotoxic" mechanism of action, causing rapid tumor cell death and inhibiting the growth of xenografted human tumor cell lines in mice. Gamitrinib were not toxic to normal cells or tissues and did not affect Hsp90 homeostasis in cellular compartments other than mitochondria.

FL-18 (p97 inhibitor FL-18) is is the first small-molecule covalent inhibitor of VCP/p97 AAA ATPase with IC50 of 59.3 nM, capable of covalent engagement of p97 with proteome-wide selectivity.FL-18 showed better inhibition potency than NMS-873, a well-known p97 inhibitor.FL-18 covalently modified C522 residue in p97 and showed potent enzymatic inhibition.FL-18 showed potent inhibition towards U87MG glioma cancer cells (IC50=31 nM).FL-18 inhibited the p97 activity and induced aggregation of ubiquitinated proteins in U87MG cells.

EN523 (EN-523) is a small molecule covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48-ubiquitin-specific deubiquitinase OTUB1, OTUB1 recruiter component of DUBTAC NJH-2-057.Deubiquitinase-targeting chimeras (DUBTACs), heterobifunctional small molecules consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, to stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner.

DI-1548 (DI 1548) is a potent, selective and covalent DCN1 inhibitor with IC50 of 4.6 nM and Ki of <1 nM, does not bind to DCN3.DI-1548 could inhibit cullin 3 neddylation at concentration as low as 1 nM, which is 1000 times more potent than DI-591.DI-1548 selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor DI-591.

DDO-6600 (DDO 6600) is a potent, selective, covalent inhibitor of Hsp90, covalently modifies Cys598 on Hsp90 and disrupts the interaction between Hsp90 and Cdc37 (IC50=6.67 uM).DDO-6600 exhibited antiproliferative activities against multiple tumor cells without inhibiting ATPase activity.DDO-6600 induced the degradation of kinase client proteins in multiple tumor cell lines, promoted apoptosis, and inhibited cell motility.DDO-6600 exhibits antitumor activity in HCT-116 mouse models.

CRL inhibitor 33-11 is a small moelcule E3 CRL inhibitor, directly and selectively binds to the purified E3 ROC1-CUL4A CTD and ROC1-CUL1 CTD complex with Kd of 0.223 and 4.53 uM, respecitvely.CRL inhibitor 33-11 binds to ROC1-CUL1 more effectively than ROC1-CUL1-Nedd8.CRL inhibitor 33-11 showed the ability to inhibit ubiquitination by ROC1–CUL1 more potently than that by ROC1-CUL1-Nedd8.CRL inhibitor 33-11 inhibited the ubiquitination of CK1α by CRL4CRBN in vitro.

CBK006377 (CBK77) is a small molecule inhibitor of the ubiquitin-proteasome system (UPS) with EC50 of 4.3 uM in MelJuSo Ub-YFP cells (6h treatment).CBK77 (16h treatment, 10 uM) causes an irreversible, global impairment of the UPS collapse, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death.CBK77 causes a global impairment of ubiquitin-dependent proteasomal degradation without global inhibition of proteasome or DUB activity.NAD(P)H:quinone oxidoreductase 1 (NQO1) is a critical factor for CBK77-mediated UPS impairment, CBK77 is an NQO1 substrate, efficiently metabolized by NQO1.CBK77 reduces growth of NQO1-proficient human cancer cells and xenograft tumors in mice without overt signs of toxicity.

BIO-2007817 is a small-molecule positive allosteric modulator of Parkin E3 ligase with EC50 of 0.17 uM (TR-FRET).BIO-2007817 stimulated Parkin autoubiquitination as measured by Western blots in a concentration-dependent manner, was also able to induce the appearance of monoubiquitinated forms of Miro1.BIO-2007817 induced the appearance of slower-migrating Parkin species in a concentration-dependent manner with maximal efficacy at 20 uM in Parkin autoubiquitination assay.BIO-2007817 does not affect the rate of Parkin translocation to mitochondria nor the number of mitochondria within lysosomes.

BC-DXI-495 is a specific small molecule inhibitor of AIMP2-DX2-HSP70 interaction, specifically reduced the levels of DX2 (IC50=4.2 uM) but not AIMP2-F, and the viability of lung cancer cells (EC50=14 uM).BC-DXI-495 bound to DX2 with KD of 14 uM.BC-DXI-495 specifically reduced the levels of endogenous DX2 protein but not of AIMP2-F , affected the DX2 protein level, but not mRNA level.BC-DXI-495 inhibited DX2-dependent cell growth, significantly diminished tumor growth in a xenograft model of H460 cells, with little effect on body weigh.BC-DXI-495 significantly suppressed the growth and weight of tumors expressing DX2 WT, but not L80A mutant.

Aminoxyrone is a novel peptidometic C-terminal HSP90 inhibitor by targeting HSP90 dimerization via the C-terminal domain (CTD) with Kd of 27.4 uM; destabilizes BCR-ABL1 without inducing HSR in vitro and in vivo, additionally reduces pAKT-S473, pS6 expression and expression of client proteins associated with HSP90 chaperone activity, involving t-AKT, t-STAT5a, t-CRKL, cMYC, and BCL2; triggers the degradation of HSP90 client proteins without elevating the expression of HSPs (HSP70, HSP40 & HSP27); significantly inhibits cell growth and induces apoptosis of human leukemic stem cells (LSCs) with average EC50 of 20.94 uM, Aminoxyrone is effective in imatinib resistant CML and lacks heat shock response.

MyoMed-205 is a small moelcule that inhibits MuRF1 (TRIM63) activity and MuRF1/MuRF2 expression.

USP7i-1 is a potent, selective USP7 inhibitor..

GRP78-IN-1 exhibits several interactions with GRP78 residues with binding energy of -8.07 kcal/mol. GRP78-IN-1 shows the potent cytotoxic, anti-proliferative in cancer cells. GRP78-IN-1 exhibits promising apoptosis in breast cancer cells and wound healing properties.

HSP70-IN-3 is a potent HSP70 inhibitor (IC50s of 1.1 and 1.9 μM in ASZ001 and C3H10T1/2, respectively). HSP70-IN-3 has anti-Hh (Hedgehog signaling) activity and anti-proliferative activity and reduces expression of the oncogenic transcription factor GLI1.

HSP90-IN-9 is a potent and selective HSP90 inhibitor. HSP90-IN-9 displays a fungicidal effect in a dose-dependent manner. HSP90-IN-9 inhibits fungal biofilm formation and fungal morphological changes after being combined with FLC. HSP90-IN-9 recovers FLC resistance by down-regulating the expression of related genes (ERG11, CDR1 and CDR2).

Apatorsen (sodium) is an antisense oligonucleotide designed to bind to Hsp27 mRNA, resulting in the inhibition of the production of Hsp27 protein.