with the compound. Selectivity over KDM4C could be explained through replacement of KDM5A A583 with KDM4C S290. The presence of I73 in KDM4C
compared to R73 in KDM5A could result in a displacement of Y409.
Further optimisation of 11 led to pyrazolo[1,5-a]pyrimidin-7(4H )-one 12, a
potent and selective inhibitor of KDM5 with improved cell potency (PC9
H3K4Me3 EC 50 ¼ 0.34 μM), which has a more balanced human plasma protein
binding (hPPB) and cell permeability [69]. 12 showed good selectivity over the other
Fig. 11 Crystal structures of KDM5 in complex with selective inhibitors. (a) Crystal structure of
10 bound in KDM5B (PDB:5A3N); (b) crystal structure of 11 bound in KDM5A (PDB:5CEH); (c)
crystal structure of 13 bound to KDM5A (PDB:5K4L); (d) crystal structure of 14 bound to KDM5A
(PDB:5V9T)
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compared to R73 in KDM5A could result in a displacement of Y409.
Further optimisation of 11 led to pyrazolo[1,5-a]pyrimidin-7(4H )-one 12, a
potent and selective inhibitor of KDM5 with improved cell potency (PC9
H3K4Me3 EC 50 ¼ 0.34 μM), which has a more balanced human plasma protein
binding (hPPB) and cell permeability [69]. 12 showed good selectivity over the other
Fig. 11 Crystal structures of KDM5 in complex with selective inhibitors. (a) Crystal structure of
10 bound in KDM5B (PDB:5A3N); (b) crystal structure of 11 bound in KDM5A (PDB:5CEH); (c)
crystal structure of 13 bound to KDM5A (PDB:5K4L); (d) crystal structure of 14 bound to KDM5A
(PDB:5V9T)
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