Table 2.

Small molecules tested in hematopoietic cells to improve HDR-mediated genome editing.

Molecule	Pathway	Molecule Target	Cells	Editing System	Target Locus	HDR Editing Results	Ref.
NU7441	NHEJ	DNA-PK inhibitor	K562	Cas9 RNP + AAV6	CD45	~2.5-fold increase	[90]
			CD34+	Cas9 RNP + AAV6	CD45	~2-fold increase
NU7026	NHEJ	DNA-PK inhibitor	K562	Cpf1 + ssODN-TNS	HPRT	~4-fold increase	[91]
			CD4+	Cpf1 + ssODN-TNS	HPRT	3-fold increase
			CD34+	Cpf1 + ssODN-TNS	HPRT	1.7-fold increase
			K562	Cas9 RNP + AAV6	CD45	No increase	[90]
M3814	NHEJ	DNA-PK inhibitor	K562	Cas9 + ssODN	FRMD7	~4-fold increase	[72]
SCR7	NHEJ	Inhibitor of ligase IV	K562	Cas9 RNP + AAV6	CD45	No increase	[90]
			CD34+	Cas9 RNP + AAV6	CD45	No increase
			CD34+	Cas9 RNP + ssODN	HBB	No increase	[27]
RS-1	HDR	RAD51 agonist	K562	Cas9 RNP + AAV6	CD45	~2.1-fold increase	[90]
			CD34+	Cas9 RNP + AAV6	CD45	No increase
			K562	Cas9 RNP + dsDNA	LAMP1 FBL	No increase	[73]
Nocodazole	Cell cycle	Inhibition of microtubule polymerization	K562	Cas9 RNP + dsDNA	LAMP1 FBL RAB11A TOMM20	~5–10% increase in FBL, RAB11A, and TOMM20	[73]
RO-3306 (RO)	Cell cycle	CDK1 inhibitor	CD34+	hGemCas9 + AAV6	HBB	Increase in ratio HDR/NHEJ: 4-fold (in vitro), 7-fold (in vivo, NSG mice)	[68]
XL413	Cell cycle	CDC7 inhibitor, extends S-phase	K562	Cas9 RNP + dsDNA	SMC1A LAMP1 HIST1H2BJ NPM1 FUS TOMM20 FBL RAB11A	~1.6 to 3.5-fold increase at all loci	[73]
			T-cells	Cas9 RNP + dsDNA	RAB11A TUBA1B CLTA	Increase at all loci in a dose dependent manner
			CD34+	Cas9 RNP + ssDNA	HBB TOMM20	Slight increase
L755507	Unknown	β3-adrenergic receptor agonist	K562	Cas9 RNP + AAV6	CD45	~1.5-fold increase	[90]

Abbreviations: mPB-HSPC: mobilized peripheral blood-HSPC; TNS: targeted nucleotide substitutions; RNP: ribonucleoprotein; ssODN: single stranded oligonucleotide; PBMCs: peripheral blood mononuclear cells; NSG: NOD/SCID/IL-2rγ^null; CDC7: cell division cycle 7; CDK1: cyclin-dependent kinase 1; DNA-PK: DNA-protein kinase; HBB: beta-globin gene; HPRT: hypoxanthine phosphoribosyltransferase 1; FRMD7: FERM domain containing 7; SMC1A: structural maintenance of chromosomes 1A; LAMP1: lysosomal associated membrane protein 1; HIST1H2BJ: histone cluster 1 H2B family member J; NPM1: nucleophosmin 1; FUS: FUS RNA binding protein; TOMM20: translocase of outer mitochondrial membrane 20; FBL: fibrillarin; TUBA1B: tubulin alpha 1b; CTLA: cytotoxic T-lymphocyte associated protein 4.