Reprogramming with Small Molecules instead of Exogenous Transcription Factors

Table 1

Small molecules that enhance iPSC generation efficiency and quality.

Target or signaling pathway	Name	Concentration	Host cells	Efficiency and necessity	Reference
HDAC inhibitor	VPA	0.5–2 mM	Mouse, human	>100-fold	Huangfu et al. (2008) [31]
HDAC inhibitor	SAHA	5 M	Mouse	10-fold	Huangfu et al. (2008) [31]
HDAC inhibitor	TSA	20 nM	Mouse	10-fold	Huangfu et al. (2008) [31]
HDAC inhibitor	Sodium butyrate	0.5–1 mM	Mouse, human	100-fold	Mali et al. (2010) [66]
DMNT inhibitor	5-aza-CR, AZA	0.5 mM	Mouse	3-fold	Mikkelsen et al. (2008) [29]
DMNT inhibitor, histone deacetylase inhibitor	RSC133	10 M	Human	3-fold	Lee et al. (2012) [10, 67]
Retinoic acid receptor agonist	AM580	100 nM	Mouse	~200-fold	Wang et al. (2011) [68]
H3K4 demethylation inhibitor (epigenetic modulator)	Tranylcypromine (Parnate)	5–10 μM	Mouse	3-fold	Li et al. (2009) [35]
Epigenetic modulators	DZNep	0.05–0.1 μM	Mouse	65-fold	Hou et al. (2013) [27]
Retinoic acid receptor ligand	TTNPB	1 μM	Mouse	15-fold	Hou et al. (2013) [27]
ALK4, ALK5, and ALK7 inhibitor	SB431542	10 uM	Human	Thiazovivin and PD0325901, ~200 fold	Lin et al. (2009) [62]
Selective MEK/ERK inhibitor	PD0325901	1 uM	Human	Thiazovivin and SB431542, ~200-fold	Lin et al. (2009) [62]
Rho-associated protein kinase inhibitor	Thiazovivin	1 uM	Human	PD0325901 and SB431542, ~200-fold	Lin et al. (2009) [62]
Rho-associated protein kinase inhibitor	Y27632	10 uM	Human	Improve generation and maintaining	Claassen et al. (2009) [69]
AKt-mediated inhibitor of GSK3-β	Compound B6	1 μM	Mouse	3-fold	Li et al. (2009) [35]
GSK-3β inhibitor, LSD1 inhibitor	LiCl	5–10 mM	Mouse and human	>10-fold	Wang et al. (2011) [68]
TGF-β inhibitor	A83-01	0.5 μM	Mouse, human	7-fold	Zhu et al. (2010) [59]
Prolyl-4-hydroxylase inhibitor	N-Oxalylglycine	1 μM	Human		Zhu et al. (2010) [59]
ALK4 inhibitor	Compound B4 (TGFb-RI)	1 μM	Mouse	4-fold	Li and Rana (2012) [70]
mTOR inhibitor	Rapamycin	0.3 nM	Mouse	4.8-fold	Chen et al. (2011) [71]
IP3K inhibitor	Compound B8	1-2 μM	Mouse	3-fold	Li et al. (2009) [35]
P38 kinase inhibitor	Compound B10	1-2 μM	Mouse	3-fold	Li and Rana (2012) [70]
cAMP agonist	Prostaglandin E2	5 μM	Mouse	Efficient in mixture	Hou et al. (2013) [27]
cAMP agonist	Rolipram	10 μM	Mouse	Efficient in mixture	Hou et al. (2013) [27]
cAMP-dependent protein kinase activator	8-Br-cAMP	0.1–0.5 mM	Human	6.5-fold	Wang et al. (2011) [68]
PDK1 activator	5-(4-Chloro-phenyl)-3-phenyl-pent-2-enoic acid (PS48)	5 μM	Human	15-fold	Zhu et al. (2010) [59]
HIF PHD1 and PHD2 inhibitor	N-Oxalylglycine	1 uM	Human	3.5-fold	Zhu et al. (2010) [59]
Phosphofructokinase 1 activator	Fructose 2,6-bisphosphate	10 mM	Human	2-fold	Zhu et al. (2010) [59]
Hypoxia-inducible factor pathway activator	Quercetin	1 μm	Human	3-fold	Zhu et al. (2010) [59]
Oxidative phosphorylation uncoupler	DNP	1 μM	Human	2-fold	Zhu et al. (2010) [59]

Note: small molecules can improve reprogramming efficiency by epigenetic modifications or signaling pathway regulation. Many of these small molecules or compound combinations can also replace c-Myc or other transcription factors. DNP, 2,4-dinitrophenol; DZNep, 3-deazaneplanocin; FSK, forskolin; HDAC, histone deacetylase; IP3K, inositol triphosphate 3-kinase; PDK1, phosphoinositide-dependent kinase 1; SAHA, suberoylanilide hydroxamic acid; TF, transcription factor; TSA, trichostatin A; VPA, valproic acid; 2-Me-5HT, 2-methyl-5-hydroxytryptamine; 5-aza-CR, AZA, 5-azacytidine; 8-Br-cAMP, 8-Bromoadenosine cyclic monophosphate.