Assessing histone demethylase inhibitors in cells: lessons learned

Hatch, Stephanie B.; Yapp, Clarence; Montenegro, Raquel C.; Savitsky, Pavel; Gamble, Vicki; Tumber, Anthony; Ruda, Gian Filippo; Bavetsias, Vassilios; Fedorov, Oleg; Atrash, Butrus; Raynaud, Florence; Lanigan, Rachel; Carmichael, LeAnne; Tomlin, Kathy; Burke, Rosemary; Westaway, Susan M.; Brown, Jack A.; Prinjha, Rab K.; Martinez, Elisabeth D.; Oppermann, Udo; Schofield, Christopher J.; Bountra, Chas; Kawamura, Akane; Blagg, Julian; Brennan, Paul E.; Rossanese, Olivia; Müller, Susanne

doi:10.1186/s13072-017-0116-6

Epigenetics & Chromatin

Table 1 In vitro and cellular IC50 of selected KDM inhibitors tested

From: Assessing histone demethylase inhibitors in cells: lessons learned

	KDM5A	KDM5B	KDM5C	KDM5D	KDM2A	KDM3A	KDM4A	KDM4B	KDM4C	KDM6B
	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)	IC₅₀ (µM)
KDOAM-20	0.010 ± 0.0030 (6)	0.007 ± 0.0030 (12)	0.019 ± 0.0050 (10)	0.019 ± 0.0040 (6)	2.2 ± 0.37 (2)	1.2 ± 0.91 (4)	0.67 ± 0.23 (2)	0.099 (1)	0.19 ± 0.081 (6)	1.4 ± 0.45 (2)
In vitro
KDOAM-20	ND	20	ND	ND	ND	ND	ND	ND	ND	ND
In cells
KDOAM-21	0.068 ± 0.010 (2)	0.094 ± 0.065 (6)	0.17 ± 0.073 (6)	ND	19 ± 10 (2)	2.6 ± 1.3 (4)	11 ± 4.5 (2)	2.5 (1)	2.8 ± 1.3 (4)	11 ± 4.6 (2)
In vitro
KDOAM-21	4.8	0.7	3.1	4	NA	NA	70	10*	17.9	NA
In cells
KDOAM-32	ND	>10 (2)	ND	ND	ND	ND	ND	ND	ND	ND
In vitro
KDOAM-32	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100
In cells
KDIPP15	0.040 ± 0.016 (2)	0.063 ± 0.028 (2)	0.26 ± 0.039 (2)	0.23 ± 0.039 (2)	>100 (2)	>100 (2)	3.9 ± 1.4 (3)	1.4 ± 0.47 (3)	5.1 ± 0.062 (4)	>100 (2)
In vitro
KDIPP15	ND	20.7	ND	ND	ND	ND	ND	ND	ND	ND
In cells
KDIPP51 (CCT364883)	0.015 ± 0.0041 (4)	0.014 ± 0.0046 (4)	0.024 ± 0.0044 (4)	0.024 ± 0.0038 (4)	8.6 ± 5.9 (2)	6.0 ± 3.9 (4)	0.126 ± 0.013 (2)	0.050 ± 0.0038 (2)	0.10 ± 0.031 (4)	44 ± 17 (3)
In vitro
KDIPP51 (CCT364883)	ND	39.9^#	ND	ND	ND	ND	ND	ND	ND	ND
In cells
CPI-455	0.16 ± 0.068 (2)	0.26 ± 0.064 (2)	7.8 ± 1.6 (2)	ND	23 ± 3.5 (2)	>100 (2)	31 (1)	44 (1)	11 ± 2.3 (2)	>100 (2)
In vitro
CPI-455	ND	60	ND	ND	ND	ND	ND	ND	ND	ND
iN cells
CCT365599	ND	0.023(2)	0.065(2)	ND	12.9^c	5.3^c	0.102 ± 0.058	0.031 ± 0.012	ND	15% at 100 µM^c
In vitro^a
CCT365599	ND	>50	ND	ND	ND	ND	10	ND	ND	ND
In cells
CCT366293	ND	>10^c	>10^c	ND	ND	ND	>10 (2)	>10 (2)	ND	ND
In vitro^a
CCT366293	ND	>100	ND	ND	ND	ND	>100	ND	ND	ND
In cells
IOX1	ND	20.6 ± 9.0 (10)	30.4 ± 13.2 (13)	ND	5 ± 3.8 (4)	0.2 ± 0.22 (30)	0.5 ± 0.4 (2)	ND	3.5 ± 2.9 (16)	1.2 ± 1.3 (55)
In vitro^a
IOX1	ND	62	ND	ND	ND	ND	ND	ND	ND	ND
In cells
JIB-04 E	ND	0.561 (1)	0.622 ± 0.05 (2)	ND	1.2 ± 0.01 (3)^d	0.65 ± 0.05 (3)	ND	ND	0.62 ± 0.02 (2)	1.04 ± 0.6 (4)
In vitro^a
JIB-04 E	ND	3	ND	ND	ND	ND	ND	ND	ND	ND
In cells
JIB-04 Z	ND	7.01 (1)	>10 (3)	ND	ND	>10 (3)	ND	ND	>10 (2)	>10 (4)
In vitro
JIB-04 Z	ND	>100	ND	ND	ND	ND	ND	ND	ND	ND
In cells

In vitro
IC50 values ± SD (number of replicates) determined by the AlphaScreen assay
^aIn vitro biochemical profiling was previously reported [11]
^bBiochemical assay protocols as previously reported [11]. CCT366293 displays assay interference above 10 μM
^cResults are from a single determination
^dResults are determined by RapidFire under low iron condition (0.2 mM)
In cells
EC50 values were determined by IF assay
Results are mean values of at least 3 independent experiments unless indicated otherwise
* Results from 2 independent experiments
^#Highest concentration was excluded from calculation

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ISSN: 1756-8935

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