Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads

Table 1 In vitro antimalarial activity of E3 ubiquitin ligase inhibitors

Compound Name	P. falciparum D6 (CQ-sensitive strain) IC₅₀ (μM)				P. falciparum W2 (CQ-resistant strain) IC50 (μM)				Vero Cell Cytotoxicity ^a	THP1 Cell Cytotoxicity ^d
	48 h	72 h	96 h	120 h	48 h	72 h	96 h	120 h	48 h	48 h
Chloroquine	0.03 ±0.001	0.02 ±0.004	0.02 ±0.001	0.02 ±0.001	0.19 ±0.004^b ****	0.19 ±0.007 ^b ***	0.20 ±0.001 ^b ****	0.19 ±0.002 ^b ***	NC	NC
Thalidomide	NA	NA	NA	NA	NA	NA	NA	NA	NC	NC
proTAME	NA	NA	NA	NA	NA	NA	NA	NA	NC	NC
NSC 66811	32.18 ±4.57	37.02 ±1.80	NA	NA	28.74 ±4.01	38.95 ±2.71	NA	NA	NC	37.8 ±4.1
Nutlin 3	12.76 ±1.34	19.43 ±0.34	15.93 ±1.24	20.02 ±4.52	18.56 ±1.6	15.72 ±0.04	15.44 ±0.54	15.59 ±2.17	NC	35.2 ±2.76^e ^f##
HLI 373	2.36 ±0.05	3.07 ±0.04	2.98 ±0.01	2.43 ±0.25	3.47 ±0.02 ^b *	4.81 ±0.41 ^b **	4.74 ±0.09 ^b **	4.04 ±0.04 ^b **	NC	23.2 ±0.07 ^e ^{f ###}
JNJ 26854165	2.17 ± 0.004	2.93 ± 0.03	1.41 ±0.03	1.46 ±0.12	1.86 ±0.03	1.74 ±0.27 ^b *	2.28 ±0.03	2.02 ±0.36	26.9 8 ± 1.96^c	22.4 ±0.56 ^e ^{f ###}
SMER 3	12.06 ± 0.68	49.04 ±0.94	NA	NA	20.58 ±5.19	23.69 ±3.53 ^b *	45.80 ±0.09	48.58 ±0.49	16.0 ±0.55	5.8 ±0.28 ^{f #}
NSC 146109	5.24 ± 0.20	4.80 ±0.05	3.09 ±0.08	2.52 ±0.39	2.07 ±0.22 ^b ****	2.63 ± 0.05 ^b ***	2.91 ±0.03	3.23 ±0.03	5.27 ±0.05	1.2 ±0.28

Antimalarial activity (IC50 values in μM) of E3 ubiquitin ligase inhibitors and CQ against asexual blood stages of the PfD6 and PfW2 was determined from the dose-response inhibition with XLFit after 48, 72, 96 and 120 h of incubation
^aCytotoxicity (IC50 values in μM) of E3 ubiquitin ligase inhibitors and CQ against Vero cells after 48 h
^dCytotoxicity (IC50 values in μM) of E3 ubiquitin ligase inhibitors and CQ against THP1 cells after 48 h. The highest concentration used for E3 ligase inhibitors and CQ was 50 μM and 500 nM respectively. Values are mean ± SEM of duplicate observations. NA, not active at the highest concentration tested. NC, not cytotoxic at the highest concentration tested
^bStatistically significant difference compared to corresponding activity against PfD6 (* p-value <0.05; ** p-value <0.01; ***p-value <0.001; **** p-value <0.0001)
^cStatistically significant difference (p-value <0.001) compared to corresponding activity against PfD6 and PfW2
^eStatistically significant difference (p-value <0.001) compared to corresponding activity against PfD6
^fStatistically significant difference (^# p-value <0.05; ^## p-value <0.01; ^### p-value <0.001; ^#### p-value <0.0001) compared to corresponding activity against PfW2

ISSN: 2050-6511