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. 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 4.

SAR Profile of the α-Substituted 2-Pyridyl Series WDR5 Inhibitors

graphic file with name nihms-1882298-t0048.jpg
compnd R5 = R6 = cLogP Kinetic Solubility (μM) Ki (nM) TR-FRETa
 Cell Proliferation Assays GI50 (nM)a
 Selectivityb
WDR5 MV4:11 MOLM-13 K562 K562/MV4:11
34 graphic file with name nihms-1882298-t0049.jpg Me 2.6 80 <0.02 11 ± 6.1 26 ± 8.8 2200 ± 2300 200
35 graphic file with name nihms-1882298-t0050.jpg Me 2.6 n.d. 0.029 ± 0.002 39 ± 9.0 110 ± 23 7800 ± 2700 200
36 graphic file with name nihms-1882298-t0051.jpg Me 3.0 65 <0.02 15 ± 4.9 36 ± 11 2600 ± 1500 170
37 graphic file with name nihms-1882298-t0052.jpg Me 3.6 66 <0.02 17 ± 6.6 43 ± 9.0 2500 ± 2100 150
38 graphic file with name nihms-1882298-t0053.jpg H 2.3 86 <0.02 9.7 ± 5.6 19 ± 6.2 1900 ± 1800 200
39 graphic file with name nihms-1882298-t0054.jpg H 2.3 n.d. 0.028 ± 0.002 39 ± 7.4 100 ± 23 12000 ± 3600 310
40 graphic file with name nihms-1882298-t0055.jpg H 2.7 55 <0.02 19 ± 5.2 37 ± 8.1 1500 ± 860 79
41 graphic file with name nihms-1882298-t0056.jpg H 3.3 60 <0.02 13 ± 5.6 27 ± 4.5 3700 ± 3100 290
a

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

b

Selectivity is defined as GI50,K562/GI50,MV4:11 and is used to generally distinguish between on- and off-target inhibition mechanisms. Not determined = n.d.