. Author manuscript; available in PMC: 2020 Feb 19.

Published in final edited form as: J Med Chem. 2018 May 23;61(11):4832–4850. doi: 10.1021/acs.jmedchem.8b00071

Table 2.

SAR and properties of N-substituted analogues of compound 3.


Compound	R₁	IC₅₀ MLL_4–43 (nM)^a	GI₅₀ (μM)^b MLL-AF9	T_1/2 (min)^c	cLogP^d
3	H	15 ± 4.9	0.40	>60	4.3
8		13 ± 0.7	0.23	9.2	3.8
9		39 ± 2.1	1.0	12	4.9
10		13 ± 4.2	0.15	21	4.1
11		18 ± 3.5	0.15	13	4.2
12		83 ± 2.8	0.25	13	4.8
13 (MI-853)		10 ± 0.7	0.075	5.7	4.5
14		44 ± 17	0.18	4.9	4.8
15		75 ± 22	0.23	14	5.4
16		57 ± 8.5	1.2	8.6	6.4
17		42 ± 2.8	0.75	10	6.9
18 (RS)		21 ± 4.2	0.25	11	3.2
19		13 ± 2.8	0.15	26	4.7
20		55 ± 15	0.25	19	5.2
21		71 ± 7.1	0.45	15	5.8
22		26 ± 2.1	0.22	53	4.7
23		32 ± 1.4	0.15	24	4.4

IC₅₀ values were measured by fluorescence polarization assay using fluorescein labeled MLL _4–43, average values from 2–3 independent measurements ± SD are provided.

Growth inhibition (GI₅₀ values) measured in the MTT cell viability assay after 7 days of treatment of murine bone marrow cells transformed with MLL-AF9.

Half-life of compounds in mouse liver microsomes.

Calculated with ChemBioDraw Ultra 14.0.