To rationalize the observed selectivity and potency, compound 22 was
co-crystallized in PI3Kγ, which served as structural platform at the time the compound was synthesized, despite no inhibitory activity measured on this isoform
(IC 50 > 10 μM). Interestingly compound 22 exhibited a different mode of binding
compared to LY-294002, adopting a propeller shape as previously described for the
selective PI3Kδ inhibitor PIK-39 in complex also with PI3Kγ despite again no
activity on this isoform [78]. In the co-crystal, compound 22 interacted classically
with the hinge Val854 NH residue via the morpholine oxygen, but more interestingly
the phenyl group was projected towards the P-loop in the so-called selectivity pocket
resulting from a movement of Met804 (Fig. 16a), a conserved residue across the
PI3Ks.
Compound 22 and other anilide derivatives suffered from lack of in vivo stability
due to rapid cleavage of the amide bond. We next generated a series of benzimidazoles derivatives and identified compound 23 as advanced lead for the project
[77]. The 3D-structure of compound 23 in complex with PI3Kδ could be obtained
and confirmed the binding mode of 22 observed in PI3Kγ. Similarly, the
corresponding methionine residue of
γ Met804 in the P-loop (
δ Met752) changed its
conformation compared to its position in the apo-structure, leaving space for the
( (W2+UI[
40%
23%
(19)
(20)
(21)
(22)
IC50 (nM)
PI3Kα :
2000
PI3Kβ :
42
PI3Kδ :
118
PI3Kγ : >10000
1/NaOH THF (100%)
2/EDCI,Pyridine (70%)
NH 2
N
O
O
N
H
O
N
H
N
N
O
O
O
O
N
H
N
O
N H
O
O
N
H
O
N
O
N H 2
O
O
+
Scheme 6 Chemical synthesis of compound 22
Fig. 16 (a) Compound 22 co-crystallized in PI3Kγ. (b) Compound 23 co-crystallized in PI3Kδ.
Ligand carbon atoms are colored in orange
114
L. Schio and H. Minoux
co-crystallized in PI3Kγ, which served as structural platform at the time the compound was synthesized, despite no inhibitory activity measured on this isoform
(IC 50 > 10 μM). Interestingly compound 22 exhibited a different mode of binding
compared to LY-294002, adopting a propeller shape as previously described for the
selective PI3Kδ inhibitor PIK-39 in complex also with PI3Kγ despite again no
activity on this isoform [78]. In the co-crystal, compound 22 interacted classically
with the hinge Val854 NH residue via the morpholine oxygen, but more interestingly
the phenyl group was projected towards the P-loop in the so-called selectivity pocket
resulting from a movement of Met804 (Fig. 16a), a conserved residue across the
PI3Ks.
Compound 22 and other anilide derivatives suffered from lack of in vivo stability
due to rapid cleavage of the amide bond. We next generated a series of benzimidazoles derivatives and identified compound 23 as advanced lead for the project
[77]. The 3D-structure of compound 23 in complex with PI3Kδ could be obtained
and confirmed the binding mode of 22 observed in PI3Kγ. Similarly, the
corresponding methionine residue of
γ Met804 in the P-loop (
δ Met752) changed its
conformation compared to its position in the apo-structure, leaving space for the
( (W2+UI[
40%
23%
(19)
(20)
(21)
(22)
IC50 (nM)
PI3Kα :
2000
PI3Kβ :
42
PI3Kδ :
118
PI3Kγ : >10000
1/NaOH THF (100%)
2/EDCI,Pyridine (70%)
NH 2
N
O
O
N
H
O
N
H
N
N
O
O
O
O
N
H
N
O
N H
O
O
N
H
O
N
O
N H 2
O
O
+
Scheme 6 Chemical synthesis of compound 22
Fig. 16 (a) Compound 22 co-crystallized in PI3Kγ. (b) Compound 23 co-crystallized in PI3Kδ.
Ligand carbon atoms are colored in orange
114
L. Schio and H. Minoux