Table 2 Structure activity relationships for CP2 analogues.

From: Highly selective inhibition of histone demethylases by de novo macrocyclic peptides

  

IC 50 (nM)

  

IC 50 (nM)

  

KDM4A

KDM4C

  

KDM4A

KDM4C

1

CP2

42

29

12

T13Z

110

60

2

Linear CP2

172

144

13

C14meC

9

23

3

DY1LY

66

78

14

T13meT

48

53

4

R6A

2,700

3,900

15

V2meV

37

60

5

R6F

5,500

>104

16

DY1meDY

264

192

6

R6AcK

2,400

5,900

17

G8DA

10

29

7

R6Cit

283

695

18

G8DA/Y124FF

10

9

8

R6K

24

112

19

CP2.1

27

15

9

R6Kme3

12

—

20

CP2.2

100

274

11

CP2(polyR)

1.8

0.8

21

CP2.3

110

69

    

22

CP2.3(R6A)

—

>104

  1. IC50, half-maximal inhibitory concentration.
  2. IC50 values were determined using the AlphaScreen method. All peptides were cyclic, except for Linear CP2. Peptides are named as derivatives of CP2 (original, residue number, modified residue). CP2.1, CP2.2 and CP2.3 contained multiple modifications (see Supplementary Fig. S6): CP2.1—G8DA/C14meC, CP2.2—V2meV/G8DA/T13meT/C14meC, CP2.3—V2meV/G8DA/Y124FF/T13P/C14meC; (meX: N methylation of X, DX: D-amino acid). IC50 value of polyR alone was 40 nM against KDM4A.
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