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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 3.

SAR Profile of the P7 Pyridylmethyl Series WDR5 Inhibitors

graphic file with name nihms-1882298-t0038.jpg
compnd R3 = R4 = cLogP Ki (nM) TR-FRETa
 Cell Proliferation Assays GI50 (nM)a
 Selectivityb
WDR5 MV4:11 MOLM-13 K562 K562/MV4:11
25 Me graphic file with name nihms-1882298-t0039.jpg 1.8 0.23 ± 0.03 1500 ± 160 3100 ± 200 >30000 >20
26 Me graphic file with name nihms-1882298-t0040.jpg 2.3 0.039 ± 0.005 170 ± 53 330 ± 120 13000 ± 2500 76
27 Me graphic file with name nihms-1882298-t0041.jpg 2.3 0.020 ± 0.004 23 ± 9.1 33 ± 12 3600 ± 310 160
28 Me graphic file with name nihms-1882298-t0042.jpg 2.3 0.59 ± 0.19 3000 ± 840 4700 ± 790 22000 ± 6500 7
29 Me graphic file with name nihms-1882298-t0043.jpg 2.3 0.064 ± 0.009 270 ± 94 550 ± 200 13000 ± 7100 48
30 Me graphic file with name nihms-1882298-t0044.jpg 1.7 <0.02 24 ± 8.6 39 ± 14 9500 ± 4800 400
31 Me graphic file with name nihms-1882298-t0045.jpg 2.8 <0.02 16 ± 7.3 25 ± 9.6 4100 ± 1300 260
32 Et graphic file with name nihms-1882298-t0046.jpg 2.3 <0.02 34 ± 18 59 ± 30 13000 ± 10000 380
33 Et graphic file with name nihms-1882298-t0047.jpg 3.4 <0.02 24 ± 8.2 43 ± 15 5600 ± 1100 230
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.