Table 1 Summary of 5,6-core series optimization guided by ligand-based relative binding (L-RB-FEP+) and protein residue mutation (PRM-FEP+) predictions
AZD1775 | Compound 2 | Compound 9 | Compound 10 | |
|---|---|---|---|---|
Chemical structure |
|
|
|
|
Wee1 L-RB-FEP+ IC50 [nM] | n/a | 25 | 4 | 0.1 |
Wee1 ADP-Glo IC50 [nM] | 0.4 | 5.3 | 7.8 | 0.7 |
PLK1 ADP-Glo IC50 [nM] | 75.7 | > 10,000 | > 10,000 | > 10,000 |
PRM-FEP+ ΔpKi | ||||
Asn → Thr | −1.9 | −0.3 | −2.1 | −2.0 |
Asn → Phe | −2.1 | 1.6 | −3.8 | −5.2 |
Asn → Met | −1.4 | 0.9 | −2.2 | −2.3 |
Asn → Leu | −3.1 | −0.2 | −3.3 | −3.7 |
Asn → Val | −1.7 | −1.1 | −0.5 | −1.2 |
Wee1 Selectivity fold (GK) | ||||
ABL1 (Thr) | >1000 | 10 | 3 | 5 |
ERK2 (Thr) | >1000 | 910 | >1000 | >1000 |
KIT (Thr) | >1000 | 290 | >1000 | >1000 |
PDGFRb (Thr) | >1000 | 7 | 40 | 150 |
CDK9 (Phe) | >1000 | 210 | >1000 | >1000 |
CLK4 (Phe) | >1000 | 16 | >1000 | >1000 |
DYRK1A (Phe) | >1000 | 50 | >1000 | >1000 |
FLT3 (Phe) | >1000 | 0.7 | >1000 | 610 |
HIPK2 (Phe) | >1000 | 20 | 940 | >1000 |
TRKA (Phe) | >1000 | 0.3 | 450 | 100 |
AKT1 (Met) | >1000 | >1000 | >1000 | >1000 |
CSNK1E (Met) | >1000 | 620 | 190 | >1000 |
JAK2 (Met) | >1000 | 12 | 130 | 77 |
MAP4K2 (Met) | >1000 | 4 | 12 | 33 |
NEK2 (Met) | >1000 | 6 | 0.8 | 54 |
AXL (Leu) | >1000 | 14 | 140 | 690 |
MERTK (Leu) | >1000 | 5 | 550 | >1000 |
RET (Val) | >1000 | 13 | 17 | 210 |
IRAK4 (Tyr) | >1000 | 16 | 400 | >1000 |
SLK (Ile) | >1000 | 14 | 10 | 110 |
Subpanel by GK < 100-fold (scanMAX by GK with %Ctrl < 10) | ||||
% Thr kinases hit | 0 (10) | 50 (14) | 50 | 25 (11) |
% Phe kinases hit | 0 (7) | 83 (19) | 0 | 0 (2) |
% Met kinases hit | 0 (3) | 60 (16) | 40 | 60 (11) |
% Leu kinases hit | 0 (4) | 100 (7) | 0 | 0 (1) |
% other kinases hit | 0 (7) | 100 (19) | 67 | 0 (9) |
scanMAX: Number of hits, Selectivity score | ||||
S(35) | 47, 0.117 | 120, 0.298 | 50, 0.124 | |
S(10) | 21, 0.052 | 60, 0.149 | 29, 0.072 | |
S(1) | 10, 0.025 | 26, 0.065 | 9, 0.022 | |
scanMAX plots |
|
|
|
