KDM families (1A, 2B, 3B, 4C, 6A, 7B) with IC 50 > 1.9 μM and also against
300 kinase panel with no activity >50% at 10 μM. The compound demonstrated a
good pharmacokinetic profile in mice and suitable for further profiling in vivo.
Superimposition of KDOAM-25 10 and CPI-455 11 in KDM5A shows that the
cyanopyrazole core is tilted from the plane of the pyridine carboxamide (Fig. 12).
The core in CPI-455 is offset by the nitrile group coordinating to the metal centre
which improves π–π stacking interactions with Y472 and 480. Y409 is displaced
away from the active site when CPI-455 is bound which highlights the improved
selectivity of CPI-455 over KDM4 in which the rigid tyrosine blocks the isopropyl
group from binding.
A hybrid compound of the pyridopyrimidinone and cyanopyrazole scaffolds was
developed by Genentech to give a series of 1,7-naphthyridone inhibitors that were
potent against KDM5 and showed good selectivity over KDM4C and KDM2B
[70]. Various substitutions were trialled at C-3 to extend into the region occupied
by isopropyl group of the cyanopyrazoles with KDM5. Introductions of electron
withdrawing groups at C-3 resulted in an increase in potency for KDM5A due to
improved interactions with K501 and N575. To lower the pKa of the ionisable proton
and improve the cell permeability, C-3 carboxamides were explored. Only small alkyl
groups on the nitrogen were tolerated due to the tight binding pocket created by S478
and Y409. 13 was identified as the most potent inhibitor against KDM5A
(IC 50 ¼ 50 nM) with excellent MCDK permeability; however, no cellular activity
was observed in a PC9 cell-based assay measuring H3K4me3 levels.
A co-crystal structure of 13 in KDM5A (PDB:5K4L) confirmed that
1,7-naphthyridones were 2OG competitive with monodentate metal coordination
of N7 (Fig. 11c). π–π stacking interactions were observed between the ring system
and Y472 and F480 and the carbonyl oxygen engaged in hydrogen bonding to Nε of
K501. Van der Waals interactions were observed between N-ethyl of C-3 amide with
Fig. 12 Overlay of 10
(green) bound in KDM5B
(green) and 11 (blue) bound
in KDM5A (blue)
242
M. Wright et al.
300 kinase panel with no activity >50% at 10 μM. The compound demonstrated a
good pharmacokinetic profile in mice and suitable for further profiling in vivo.
Superimposition of KDOAM-25 10 and CPI-455 11 in KDM5A shows that the
cyanopyrazole core is tilted from the plane of the pyridine carboxamide (Fig. 12).
The core in CPI-455 is offset by the nitrile group coordinating to the metal centre
which improves π–π stacking interactions with Y472 and 480. Y409 is displaced
away from the active site when CPI-455 is bound which highlights the improved
selectivity of CPI-455 over KDM4 in which the rigid tyrosine blocks the isopropyl
group from binding.
A hybrid compound of the pyridopyrimidinone and cyanopyrazole scaffolds was
developed by Genentech to give a series of 1,7-naphthyridone inhibitors that were
potent against KDM5 and showed good selectivity over KDM4C and KDM2B
[70]. Various substitutions were trialled at C-3 to extend into the region occupied
by isopropyl group of the cyanopyrazoles with KDM5. Introductions of electron
withdrawing groups at C-3 resulted in an increase in potency for KDM5A due to
improved interactions with K501 and N575. To lower the pKa of the ionisable proton
and improve the cell permeability, C-3 carboxamides were explored. Only small alkyl
groups on the nitrogen were tolerated due to the tight binding pocket created by S478
and Y409. 13 was identified as the most potent inhibitor against KDM5A
(IC 50 ¼ 50 nM) with excellent MCDK permeability; however, no cellular activity
was observed in a PC9 cell-based assay measuring H3K4me3 levels.
A co-crystal structure of 13 in KDM5A (PDB:5K4L) confirmed that
1,7-naphthyridones were 2OG competitive with monodentate metal coordination
of N7 (Fig. 11c). π–π stacking interactions were observed between the ring system
and Y472 and F480 and the carbonyl oxygen engaged in hydrogen bonding to Nε of
K501. Van der Waals interactions were observed between N-ethyl of C-3 amide with
Fig. 12 Overlay of 10
(green) bound in KDM5B
(green) and 11 (blue) bound
in KDM5A (blue)
242
M. Wright et al.