TABLE 3.
Multi‐ALDH (aldehyde dehydrogenase) isoform inhibitors
| Inhibitor | Target | Cellular activity | Animal/clinical studies | Ref. |
|---|---|---|---|---|
| DSF | Irreversible ALDH inhibitor | IC50: 0.15 μM for ALDH1, and 1.45 μM for ALDH2 | DSF/Cu can inhibit ALDH‐positive NSCLC tumors. The combination of DSF and gemcitabine efficiently inhibits breast tumors; the combination of TMZ and DSF/Cu in a Phase II clinical trial (NCT03034135) rescue ALDH1A3‐mediated TMZ resistance in GBM patients | 243 , 244 , 245 , 246 , 247 |
| DEAB | A reversible substrate for ALDH1A1 and ALDH3A1, and displays competitive inhibition of ALDH1A1, ALDH1A3, ALDH1B1, and ALDH5A1 | IC50: 57 nM for ALDH1A1, 1.2 μM for ALDH1A2, 3 μM for ALDH1A3, 1.2 μM for ALDH1B1, 0.16 μM for ALDH2, and 13 μM for ALDH5A1 | Inhibition of tumor growth and pulmonary metastasis in breast cancer tumors | 95 , 248 |
| DIMATE | ALDH1 and ALDH3 subfamilies | IC50: 5 μM for ALDH1A1 and ALDH3A1 | DIMATE is effective at a dose of 14 mg/kg daily given via intraperitoneal injection in PCa tumors | 249 , 250 |
| Citral | Reversible noncompetitive ALDH inhibition | Potent inhibitory activity against ALDH1A1, ALDH1A3, and ALDH2 | Nanoparticle encapsulated citral reduces the tumor growth of ALDH1A3‐overexpressing MDA‐MB‐231 xenografts | 250 , 251 |
| Aldi‐1–4 | Covalent ALDH inhibition | IC50: range from 2.2 to 7.9 μM for ALDH1A1, 5.4 to 8.6 μM for ALDH2, and 1.7 to 12 μM for ALDH3A1 | No in vivo studies | 252 |
| Aldi‐6 | Covalent ALDH inhibition | IC50: 600 nM for ALDH1A1, 800 nM for ALDH2, and 1 μM for ALDH3A1 | The combination of Aldi‐6 and cisplatin results in a greater reduction in tumor burden in HNSCCs | 253 |
| Dyclonine | Covalent ALDH inhibition | IC50: 35 μM for ALDH2, and 76 μM for ALDH3A1 | The combination of dyclonine and sulfasalazine efficiently suppresses the growth of ALDH3A1‐expressing HNSCC or GC tumors | 252 , 254 |
Abbreviations: DEAB, diethylaminobenzaldehyde; DIMATE, 4‐dimethylamino‐4‐methyl‐pent‐2‐ynthioic acid‐S‐methylester; DSF, disulfiram; GBM, glioblastoma; GC, gastric cancer; HNSCC, head‐and‐neck squamous cell carcinoma; IC50, inhibitory concentration; NSCLC, non‐small cell lung cancers; PCa, prostate cancer; TMZ, temozolomide.