Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets
Abstract
1. Introduction
2. Protein Disulfide Isomerases as a Druggable Vulnerability in a Subset of Human Cancers
3. Roles of Strongly Selective Disulfide Isomerases in Protein Folding and Cellular Signaling
4. Small Molecule Inhibitors of Strongly Selective and Non-Canonical Disulfide Isomerases
5. DDAs: Disulfide Isomerase Inhibitors with a Unique Selectivity Profile
6. Unanswered Questions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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PDIA# | Alternate Names | Catalytic Motif(s) | ER Retention Sequence | Strongly Selective in DepMap (6/16/25) | Confirmed as DDA Targets | Highly Expressed (The Human Protein Atlas; 6/16/25) |
---|---|---|---|---|---|---|
1 | P4HB | CGHC, CGHC | –KDEL | – | + | Liver, Pancreas |
2 | PDA2, PDIp | CGHC, CTHC | –KEEL | – | – | Pancreas |
3 | ERp57 | CGHC, CGHC | –QEDL | – | – | Thyroid Gland |
4 | ERp72 | CGHC, CGHC, CGHC | –KEEL | – | – | (Broadly Expressed) |
5 | PDIR | CSMC, CGHC, CPHC | –KEEL | – | – | Liver |
6 | ERp5 | CGHC, CGHC | –KDEL | +CRISPR | – | (Broadly Expressed) |
7 | PDILT | – | –KEEL | +RNAi | – | Stomach |
8 | ERp27 | – | –KTEL | +RNAi | – | Pancreas |
9 | ERp29 | – | –KEEL | – | – | (Broadly Expressed) |
10 | ERp44, TXNDC4 | CRFS | –RDEL | +CRISPR +RNAi | + | (Broadly Expressed) |
11 | TMX1 | CPAC | Transmembrane | +CRISPR | – | (Broadly Expressed) |
12 | TMX2 | – | Transmembrane | – | – | (Broadly Expressed) |
13 | TMX3 | CGHC | Transmembrane | – | – | (Broadly Expressed) |
14 | TMX4 | CPSC | Transmembrane | – | – | (Broadly Expressed) |
15 | TXNDC5, ERp46 | CGHC, CGHC, CGHC | –KDEL | – | – | (Broadly Expressed) |
16 | TXNDC12, AGR1 | CGAC | –KTEL | – | – | (Broadly Expressed) |
17 | AGR2 | CPHS | –KTEL | +CRISPR +RNAi | + | Cervix, Intestine, Stomach |
18 | AGR3 | CQYS | –QSEL | +CRISPR | + | Fallopian Tube, Intestine, Lung |
19 | DnaJC10, DnaJ | CSHC, CPPC, CHPC, CGPC | –KDEL | – | – | Epididymis |
PDIB1 | Calsequestrin 1 | – | – | +RNAi | – | Skeletal Muscle, Tongue |
PDIB2 | Calsequestrin 2 | – | – | +RNAi | – | Heart Muscle |
TMX5, TXNDC15 | CRFS | Transmembrane | – | – | (Broadly Expressed) |
AGR2 Selectively Dependent Cancer Line | AGR2 Essentiality Rank (out of 17,347 Genes) | Tumor Type | Other Top 10 Essential Genes (Rank) |
---|---|---|---|
C80 | 1 | Colorectal | CDX2 (2) |
COLO205 | 3 | Colorectal | FOXP4 (2), FOXA2 (9) |
LS513 | 3 | Colorectal | CDX2 (2), CDX1 (5) |
SNUC4 | 5 | Colorectal | Axin1 (8) |
MAPACHS77 | 2 | Pancreatic | FZD5 (1), WNT7B (3), DVL1 (4), PORCN (6), WLS (7), LRP5 (8) |
HSC39 | 7 | Esophagogastric | |
2313287 | 8 | Gastric | AXIN2 (9) |
Rank | Gene |
---|---|
1 | SOX9 |
2 | AGR3 |
3 | TTC7A |
4 | TCF7L2 (Wnt effector) |
5 | KDELR3 |
Rank | Gene | Importance | Corr. Type |
---|---|---|---|
1 | ERN2 (IRE1β) | 22.5% | – |
2 | MUC3A | 2.4% | – |
3 | LRRC19 | 1.6% | – |
4 | SH3BGRL2 | 1.3% | – |
5 | TCEA2 | 1.2% | + |
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Law, M.E.; Dulloo, Z.M.; Hardy, B.; Kelegama, A.; Clark, R.; Rivas Montbrun, M.; Antmann, G.; Nooka, S.; Castellano, R.K.; Law, B.K. Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets. Biomolecules 2025, 15, 1146. https://doi.org/10.3390/biom15081146
Law ME, Dulloo ZM, Hardy B, Kelegama A, Clark R, Rivas Montbrun M, Antmann G, Nooka S, Castellano RK, Law BK. Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets. Biomolecules. 2025; 15(8):1146. https://doi.org/10.3390/biom15081146
Chicago/Turabian StyleLaw, Mary E., Zaafir M. Dulloo, Brian Hardy, Ania Kelegama, Reagan Clark, Mariana Rivas Montbrun, Gabriella Antmann, Srihith Nooka, Ronald K. Castellano, and Brian K. Law. 2025. "Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets" Biomolecules 15, no. 8: 1146. https://doi.org/10.3390/biom15081146
APA StyleLaw, M. E., Dulloo, Z. M., Hardy, B., Kelegama, A., Clark, R., Rivas Montbrun, M., Antmann, G., Nooka, S., Castellano, R. K., & Law, B. K. (2025). Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets. Biomolecules, 15(8), 1146. https://doi.org/10.3390/biom15081146