Table 3 Summary of tricyclic core series optimization guided by ligand-based relative binding (L-RB-FEP+) and protein residue mutation (PRM-FEP+) predictions
Compound 8 | Compound 13 | Compound 14 | |
|---|---|---|---|
Chemical structure |
|
|
|
Wee1 L-RB-FEP+ IC50 [nM] | n/a | 2 | 0.5 |
Wee1 ADP-Glo IC50 [nM] | 0.6 | 42.3 | 1.0 |
PLK1 ADP-Glo IC50 [nM] | > 10,000 | > 10,000 | > 10,000 |
PRM-FEP+ ΔpKi | |||
Asn → Thr | −1.1 | −2.0 | −2.0 |
Asn → Phe | −4.0 | −3.8 | −4.2 |
Asn → Met | −1.8 | −2.5 | −2.4 |
Asn → Leu | −3.6 | −4.0 | −3.8 |
Asn → Val | −1.9 | −2.5 | −3.0 |
Subpanel by GK < 100-fold (scanMAX by GK with %Ctrl < 10) | |||
% Thr kinases hit | 0 (4) | 0 | 25 (11) |
% Phe kinases hit | 0 (2) | 0 | 0 (1) |
% Met kinases hit | 0 (1) | 0 | 0 (3) |
% Leu kinases hit | 0 (1) | 0 | 0 (1) |
% other kinases hit | 0 (5) | 0 | 0 (5) |
scanMAX: number of hits, selectivity score | |||
S(35) | 20, 0.05 | 29, 0.072 | |
S(10) | 8, 0.02 | 14, 0.035 | |
S(1) | 4, 0.01 | 5, 0.012 | |
scanMAX plots |
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