Table 1.
Chemical modifier screens
| Phenotype | Expressed protein | Assay system | Hits | Secondary assays | Ref. |
|---|---|---|---|---|---|
| HSF-1 activation | ~1 × 106 compound screen in HeLa cells | A1, A3, C1, D1, F1 | Mammalian cellular and Caenorhabditis elegans models of HD | [51] | |
| HSF-1 activation | 10,000 compound library screen in yeast | HSF1A (TRiC/CCT complex) | Mammalian cellular and Drosophila models of HD | [52] | |
| Fly motor defect | HTT Q128 | 521 quinazoline-derived compound screen in Drosophila neurons | EVP4593 | Medium spiny neurons | [81] |
| Toxicity | HTT480 Q68 | 40,000 compounds in primary striatal neuron culture | [56] | ||
| Toxicity | HTTN90 Q8 and Q73 | ~400 selected small molecule screen in primary cultures of cortical and striatal neurons | Inhibitors of Rho kinase, phosphodiesterase, adenosine 2A receptor, and IKKβ | [57] | |
| Toxicity | HTT588 Q138 and Q15 | ~2600 small molecule screen in Drosophila primary neuronal culture | Camptothecin, OH-camptothecin, 18β-glycyrrhetinic acid, and carbenoxolone | Drosophila HD model | [66] |
| Toxicity | HTT exon 1 Q25- and Q103-EGFP | 68,887 compound screen in PC12 cells | 16F16, thiomuscimol, cystamine | Cortico-striatal brain slice models of HD and AD | [61] |
| Toxicity | HTTN90 Q73 | 74 drug-like compound screen in rat brain slices | Inhibitors of IKK complex, CXCR3 chemokine receptor, c-Jun N-terminal kinase, and adenosine 2A receptor | [60] | |
| Toxicity | HTT exon 1 Q150 | 9 selected compound screen in C. elegans ASH neurons | LiCl, TSA, SAHA, and mithramycin | [80] | |
| Aggregation and toxicity | HTT Q103-EGFP | 16,000 compound library screen in yeast | C2-8 | Mammalian cells, brain-slice, and Drosophila models of HD; R6/2 transgenic mouse | [41] |
| Aggregation | GST-HTT exon 1 Q51 | In vitro screen of ~184,000 small molecule library screen | Benzothiazoles | 293 Tet-Off cells | [21] |
| Aggregation | HTT171 Q58 | In vitro screen of 1040 FDA-approved drugs and bioactive compounds | Gossypol, gambogic acid, juglone, celastrol, sanguinarine, and anthralin | HdhQ111/Q111 striatal cells | [22] |
| Aggregation | GST-Q62 | In vitro screen of peptide phage display library | Six tryptophan-rich peptides (polyQ-binding peptide 1) | COS-7 cell model of HD | [23] |
| Aggregation | GST-HTT exon 1 Q51 | In vitro screen of ~5000 natural substances | EGCG and related polyphenols | Yeast and Drosophila models of HD | [24] |
| Aggregation | AR127 Q65 | In vitro screen of 2800 biologically active compounds | Y-27632 | Drosophila model of HD | [25] |
| Aggregation | GST-HTT exon 1 Q51 | In vitro screen of 11 small molecules | Congo red, thioflavine S, chrysamine G, and Direct fast yellow | COS-7 cells transfected with HTT 52Q | [26] |
| Aggregation | HTTNT fragment | In vitro screen of 15 peptides | HTTNT-based peptides | SH-SY5Y cells | [27] |
| Aggregation | HTTQ72-Luciferase | 2687 small molecule screen in HEK-293 cells | Leflunomide and teriflunomide | [40] | |
| Degradation (clearance) | HTT573 Q72 | 10,000 natural compound library screen in HN10 neuronal cell line | TSA analogue, staurosporine, anisomycin, cycloheximide, borrelidin, BAY 61-3606 | [46] | |
| Degradation (clearance) | HTT573 Q72 and Q25 | ~2 × 106 compound screen in HN10 neuronal cell line | Heat shock protein 90 inhibitors | HdhQ150 embryonic stem cells and in embryonic stem cell-derived neurons | [48] |
Blank entry indicates not included in the study.
HSF = heat shock factor; HTT = huntingtin; TriC/CCT = chaperonin containing TCP-1; EGFP = enhanced green fluorescent protein; GST = glutathione-S-transferase; FDA = Food and Drug Administration; HEK = human embryonic kidney; IKKβ = IκB kinase; CXCR3 = chemokine (C-X-C motif) receptor 3; LiCl = lithium chloride; TSA = trichostatin A; SAHA = suberoylanilide hydroxamic acid; EGCG = (−)-epigallocatechin-3-gallate; AR = androgen receptor; HD = Huntington’s disease; AD = Alzheimer’s disease.