Table 1.
Summary of HDR-enhancing small molecules.
| Small Molecule | Target | Mechanism | Effect on HDR | Reference |
|---|---|---|---|---|
| SCR7 | Inhibition of NHEJ | Inhibition of ligase IV | Decrease NHEJ repair and increase HDR in several cell lines and mice and rats with ds and ss donors | [9], [10], [11], [12], [13], [14] |
| i53 | Inhibition of NHEJ | Inhibition of 53BP1, an important regulator of the DSB repair pathway | Increased HDR by 5–6 fold with ss and ds donors | [15] |
| STL127705 | Inhibition of NHEJ | Inhibitor of the DNA repair protein Ku70/80 | 2.8 to 7.2-fold and 2.3 to 4-fold increase in genome editing with Cas9n and Cpf1, respectively | [16], [17] |
| KU0060648 | Inhibition of NHEJ | Inhibition of DNA-protein kinase catalytic subunits | Increased HDR in HEK293T cells with reduced NHEJ frequency | [18] |
| NU7026 | Inhibition of NHEJ | Inhibition of DNA-protein kinase catalytic subunits | Reduced NHEJ frequency with increased KI efficiency in hiPSCs using Cas9 or Cpf1 | [19] |
| NU7441 | Inhibition of NHEJ | Inhibition of DNA-protein kinase catalytic subunits | Increased HDR in HEK293T and hiPSCs by 13.4 fold in zebrafish embryos | [18], [20], [21] |
| VE-822 | Inhibition of NHEJ | Inhibition of ataxia telangiectasia mutated and Rad3-related kinase (ATR) | 5.9-fold increased HDR in hiPSCs with ss and ds donors after DSB induced by Cpf1 | [22] |
| AZD7762 | Inhibition of NHEJ | Inhibitor of checkpoint kinase CHEK1 | 2.7-fold increased HDR in hiPSCs with ss and ds donors after DSB induced by Cpf1 | [22] |
| M3814 | Inhibition of NHEJ | Inhibition of DNA-protein kinase catalytic subunits | Increased KI in hiPSC and K562 cells using Cas9 or Cpf1 | [23] |
| RS-1 | Direct increase of HDR | Enhance binding of RAD51 with ssDNA | Increased HDR in HEK293T cells, HeLa cells, and rabbit and bovine embryos | [24], [25], [26], [27] |
| Mimosin, thymidine, hydroxy urea, lovastatin | Regulation of cell cycle | G1/S blocker | Increased HDR in neonatal fibroblasts | [6] |
| Nocodazole | Regulation of cell cycle | G2/M blocker | Increased HDR in HEK293T and hPSC using ss or ds donors | [6], [20] |
| XL413 | Regulation of cell cycle | G1/S blocker | Increased HDR in HSPCs, K562 cells, and T cells with ss or ds donors | [28] |
| Aphidicolin | Regulation of cell cycle | G1/S blocker | Increased HDR in HEK293T and neonatal fibroblasts using ss donor | [6] |
| ABT263 | Regulation of cell survival | BCL inhibitor | 70% increase in HDR in hiPSC | [29] |
| ABT751 | Regulation of cell cycle | G2/M blocker | Increased HDR in hPSCs with ds donor | [7] |
| Valproic acid (VPA) | Undetermined pathway | Histone deacetylase inhibitor | Increased HDR in hESCs with ds donor | [30] |
| Resveratrol | Suppression of NHEJ | Downregulation of LIG4, PRKDC, KU70, and KU80 | Increased HDR in porcine fetal fibroblast using ds donor | [14] |
| Brefeldin A | Undetermined pathway | Inhibition of intracellular transport from ER to golgi | Increased HDR in mouse ESCs using ds donor | [31] |
| L755507 | Undermined pathway | Agonist for β3-adrenergic receptor | Increased HDR in mouse ESCs using ds donor | [14], [31] |
**NHEJ – non-homologous end joining; HDR – homology-directed repair; ss – single stranded; ds – double stranded; hiPSCs – human-induced pluripotent stem cells; hPSCs – human pluripotent stem cells; ESCs – embryonic stem cell; KI – knock-in; ER – endoplasmic reticulum.