Research Advances in Kinase Enzymes and Inhibitors for Cardiovascular Disease Treatment

Figures & data

Figure 1.  The most important kinase targets that have been previously reported as kinase targets for heart disease treatment.

CVD: Cardiovascular disease.

Table 1.  Calcium calmodulin serine/threonine kinase IIδ inhibitors in cardiac muscle.

No.	Structure	Inhibitor class	Study year	Activity IC50
1		Natural	2012	112 µM
2		Semisynthetic	2012	1.49 µM
3		Synthetic	1990	500 nM
4		Synthetic	1996	1.57 µM
5		Group of aryl indolyl–maleimide scaffold, synthetic inhibitors	2008	10 nM to >20 µM
6		Most active aryl indolyl–inhibitor against CaMK IIδ	2008	10 nM
7		Synthetic	2012	12 nM
8		Homology modeling synthesis of pyrimidine-based inhibitors	2008	0.009–3 µM
9		Most active pyrimidine-based inhibitor	2008	9 nM
10		Synthetic	2012	2 nM
11		Inhibitor resulted from ligand-based virtual screening CaMK IIδ inhibitor	2011	20 nM
12		Inhibitor resulted from ligand-based virtual screening CaMK IIδ inhibitor	2011	82 nM

CaMK-IIδ: Calcium calmodulin serine/threonine kinase IIδ.

Table 2.  Rho kinase inhibitors.

No.	Structure	Inhibitor class	Publication year	Activity
13		HTS compound	2008	IC50 = 7.2 nM
14		Synthetic ‘isoquinoline prototype’	1997	Ki = 330 nM
15		Fasudil derivative approved for glaucoma treatment in Japan	2014	ROCK-I (IC50 = 51 nM); ROCK-II (IC50 = 19 nM)
16		Synthetic ‘isoquinoline series’	1997	Ki = 1.6 nM
17		Synthetic ‘4-aminopyridine series’	1997	Ki = 0.14 µM
18		Synthetic ‘pyrrolopyridine series’	2007	ROCK-II (IC50 = 3.6 nM)
19		Synthetic ‘indazole series’	2006	IC50 = 13 nM
20		Synthetic benzadioxane-based compound	2008	ROCK-I (IC50 = 56 nM)
21		Tetrahydroisoquinoline-based inhibitor	2010	ROCK-II (IC50 <1 nM)
22		Selective ROCK-II inhibitor	2011	ROCK-II (IC50 = 1.7 nM)
23		Tricyclic pyridocarboxamide derivatives	2015	ROCK-II (IC50 = 1 nM)
24		Structure-based drug design inhibitor	2014	IC50 = 1.5 μM
25		Structure-based design inhibitor	2013	ROCK-II (IC50 = 0.02 μM)
26		Ligand-based drug design inhibitor	2011	ROCK-II (IC50 = 0.02 μM)

HTS: High-throughput screening; ROCK: Rho kinase.

Table 3.  Protein kinase C inhibitors.

No.	Structure	Inhibitor class	Publication year	Activity
27		Natural inhibitor (Staurosporine)	1977, first isolated; 1986, the inhibitory activity against PKC was revealed	PKC (IC50 = 2.7 nM)
28		Semisynthetic (K-252 a)	1986	IC50 = 18–25 nM
29		Semisynthetic (K-252b)	1986	IC50 = 20 nM
30		Semisynthetic, 7-oxo Staurosporine (RK –1409)	1992	IC50 ≈ 1 nM
31		Natural (Calphostin C)	1989	IC50 = 0.05 µM
32		Synthetic (AEB071)	2009	PKC-α (IC50 = 2.1 nM) PKC-∊ (IC50 = 6.1 nM)
33		Synthetic	2011	PKC-α (IC50 = 829 nM) PKC-∊ (IC50 = 5 nM)
34		Synthetic	2011	PKC-βII (Ki = 29 nM)
35		Flosequinan-selective PKC inhibitor	1992	–
36		Ruboxistaurin	2006	PKC-βI (IC50 = 4.7 nM) PKC-βII (IC50 = 5.9 nM)

PKC: Protein kinase C

Table 4.  MAPK inhibitors.

No.	Structure	Inhibitor class	Publication year	Activity
37		Synthetic (SB 203580)	1996	IC50 = 0.3–0.5 µM
38		Synthetic (SB 220025)	1998	IC50 = 60 nM
39		Synthetic (RWJ 67657)	1999	p38α (IC50 = 1 μM) p38β (IC50 = 11 μM)
40		Synthetic (VX-702)	2007	p38α (IC50 = 4–20 nM)
41		Synthetic (Scio-469)	2006	p38α (IC50 = 9 nM)
42		Synthetic Dilmapimod (SB681323)	2005	Under study in early phase
43		Synthetic	2007	IC50 = 3 nM
44		Synthetic	2007	IC50 = 3 nM
45		BMS582949	2006–2015	p38α (IC50 = 13 nM)
46		Synthetic (VX-745)	1999	p38α (IC50 = 5 nM)

Table 5.  Inhibitors of glycogen synthase kinase-3β.

No.	Structure	Inhibitor class	Publication year	Activity
47		Natural (hymenialdisine)	2000	IC50 = 0.01 µM
48		Natural (5-iodo-indirubin-3’-monoxime)	2001	IC50 = 0.009 nM
49		Synthetic (alesterpaullone)	2000	IC50 = 0.004 nM
50		Synthetic (aloisine A)	2002	IC50 = 0.65 µM
51		Synthetic	2003	IC50 = 0.018 µM

Figure 2.  Five PI3K/AKT/eNOS activators.

Compound 52: resveratrol; compound 53: the cardiac glycosides (ouabain).