. Author manuscript; available in PMC: 2023 Apr 28.

Published in final edited form as: J Med Chem. 2022 Apr 18;65(8):6287–6312. doi: 10.1021/acs.jmedchem.2c00195

Table 2.

SAR Profile of Nonbasic Warhead Series



compnd	R² =	cLogP	K_i (nM) TR-FRET^a	Cell Proliferation Assays GI₅₀ (nM)^a			Selectivity^b
compnd	R² =	cLogP	WDR5	MV4:11	MOLM-13	K562	K562/MV4:11

16		2.9	<0.02	59 ± 5.6	180 ± 51	9100 ± 2100	150
17		3.9	>6.7	22000 ± 6000	20000 ± 5400	>30000	>1
18		4.4	>6.7	15000 ± 4000	15000 ± 3600	>30000	>2
19		1.6	6.5 ± 1.7	16000 ± 1300	>30000	>30000	>2
20		3.1	<0.02	32 ± 13	110 ± 33	3700 ± 2500	120
21		3.7	0.022 ± 0.001	94 ± 10	240 ± 53	7500 ± 1300	80
22		4.1	3.4 ± 0.17	4700 ± 500	7700 ± 2000	16000 ± 3100	3
23		3.6	0.028 ± 0.002	240 ± 64	710 ± 140	8500 ± 2000	35
24		3.1	>6.7	12000 ± 2800	20000 ± 4900	>30000	>3

TR-FRET K_i and cell proliferation GI₅₀ values represent four independent replicate determinations ± standard deviation.

Selectivity is defined as GI_50,K562/GI_50,MV4:11 and is used to generally distinguish between on- and off-target inhibition mechanisms.