Table 4 Summary of AZD1775 R1 exploration guided by ligand-based relative binding (L-RB-FEP+) and protein residue mutation (PRM-FEP+) predictions

From: Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study

 

AZD1775

Compound 16

Compound 17

Chemical structure

 Wee1 L-RB-FEP+ IC50 [nM]

n/a

n/a

47

 Wee1 ADP-Glo IC50 [nM]

0.4

2.3

0.2

 PLK1 ADP-Glo IC50 [nM]

76

1,079

>10,000

PRM-FEP+ ΔpKi

   

 Asn → Thr

−1.9

−0.5

−1.0

 Asn → Phe

−2.1

0.3

−3.0

 Asn → Met

−1.4

−0.4

−1.6

 Asn → Leu

−3.1

−1.1

−3.0

 Asn → Val

−1.7

−1.2

−0.4

Subpanel by GK < 100-fold

   

 % Thr kinases hit

0

50

0

 % Phe kinases hit

0

33

0

 % Met kinases hit

0

0

0

 % Leu kinases hit

0

0

0

 % other kinases hit

0

0

0

  1. Increasingly negative PRM-FEP+ ΔpKi values predict more selective inhibition of Wee1 over the off-target kinases. % kinases hit are calculated as described in Table 1.
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