mTOR Kinase: A Possible Pharmacological Target in the Management of Chronic Pain

Table 1

mTOR inhibitor drugs.

Classes	Drugs	mTOR (in vitro kinase IC50)	mTORC1 (cellular potency EC50)	mTORC2 (cellular potency EC50)	Class I PI3K (in vitro kinase IC50)	References
	Rapamycin	1.74 M (2 nM^1, in presence of FKBP12)	0.4–3.5 nM^2			[82–84]
Rapalogs	RAD001		0.4–3.5 nM^2			[82]
	CCI-779	1.76 M	<20 nM	10–20 M		[84]
	AP23573		0.2 nM			[85]
ATP-competitive mTOR inhibitors (first generation)	KU-0063794	2.5 nM^1	660 nM^3	240 nM^3	>5.3–>30 M	[86–88]
	PP242^4	8 nM		300–400 nM	0.10–2.2 M	[89, 90]
	PP30^4	80 nM			0.68–5.8 M	[89]
	Torin 1^4	4.3 nM	2–10 nM	2–10 nM	0.17–>10 M	[90, 91]
	WEY-600^4	9 nM^1	300 nM	1 M	1.96–8.45 M	[92]
	WYE-354^4	5 nM^1	300 nM	1 M	1.89–7.37 M	[92]
	CC214-1	2 nM	40 nM	18 nM	1.38 M	[93]
	OSI-027^4	4 nM			0.42–>30 M	[94]
	X-387^4	23 nM^1			0.12–>0.3 M	[95]
ATP-competitive mTOR inhibitors (second generation)	AZ8055	0.13 nM^1	27 nM^3	24 nM^3	3.2–18.9 M	[42, 88]
	AZ2014	2.8 nM^1	200 nM^3	80 nM^3	3.8–>30 M	[88]
	INK128/MLN0128^4	1 nM	<10 nM	<10 nM	0.22–5.29 M	[96]
	WYE-125132	0.19 nM^1	20 nM	200 nM	1.18–>10 M	[97]
	CC214-2	106 nM	386 nM	315 nM	>30 M	[93]
ATP-competitive mTOR/PI3K dual inhibitors	Wortmannin	0.2 M^1			0.1 nM	[83, 98]
	LY294002/SF1101^5	1.5 M^1			0.5–1.6 M	[83, 99–101]
	PI-103^5		In vitro kinase IC50: 20 nM	In vitro kinase IC50: 83 nM	2–15 nM	[40, 100, 101]
	Torin 2	2.81 nM	0.25 nM	10 nM	4.68–17.5 nM	[102, 103]
	GSK2126458	ND	Low nM	0.18–0.41 nM	0.04 nM	[104]
	NVP-BEZ235^5	20.7 nM	<250 nM	8 nM	4–75 nM	[43, 101]
	NVP-BGT226^6				4–63 nM	[105]
	SF1126 (RDGS conjugated SF1101)				Not significant inhibitory activity until hydrolyzed to SF1101	[106]
	PKI587	1.4 nM^1	<30 nM	<10 nM	0.6–8 nM	[107]

In vitro mTOR kinase IC50 was evaluated using either the immunoprecipitated or the recombinant full length enzyme. Cellular potency for the two different mTOR complexes was calculated after short term incubation, ranging between 30 min and 2 h, of different cell lines with mTOR inhibitors and subsequent analysis of the phosphorylation status of specific mTORC1 (S6K or S6) or mTORC2 (AKT, at Ser₄₇₃) substrates. In vitro PI3K and PIKK IC50 were measured using specific biochemical assays.
¹A truncated mTOR enzyme was used in the in vitro kinase assay.
²Cellular potency was evaluated by inhibition of cell proliferation, using vascular smooth muscle cells stimulated by fetal calf serum.
³Cellular potency was evaluated using a high throughput immunocytochemical assay, carried out in the MDA-MB-468 cell line.
⁴Ratio between PI3K and mTOR IC50 is <500.
⁵The reader should also consider IC50 values reported by Hayakawa et al., 2007 [99], and Kong et al., 2009 [101].
⁶NVP-226 is considered a dual mTOR/PI3K inhibitor. However, in vitro preclinical data on the mTOR inhibitory activity for this compound were not found through Medline Search.