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Table 1 Activity of tyrosine kinase inhibitors against wild-type and mutated kinases, expressed as IC50 (nM) in cellular assays

From: Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy

 

Kinase

TKI

Imatinib

Nilotinib

Dasatinib

Bosutinib

Ponatinib

Bafetinib

Rebastinib

Tozasertib

Danusertib

HG-7-85-01

GNF-2 + dasatinib (dasatinib concentration)

GNF-5 + nilotinib (nilotinib concentration)

 

Abl

 
 

 WT

100–500

< 10–25

0.8–1.8

41.6

0.5

72

19–80

10–104

26–360

58.5

100 (2 nM)

30 (1 μM)

P-loop

 M244V

1600–3100

38–39

1.3

147.4

2.2

240

78–90

     

 L248V

1866–10,000

49.5–919

9.4

145.6

1.7

      

 G250E

1350–> 20,000

48–219

1.8–8.1

179.2

4.1

160

98–600

180

   

 Q252H

734–3120

16–70

3.4–5.6

33.7

2.2

410

24–190

130

 

50–100

 

 Y253F

> 6400–8953

182–725

6.3–11

40

2.8

81

39

80

   

 Y253H

> 6400–17,700

450–1300

1.3–10

24.9

6.2

 

56–300

190

 

500–1000

 

 E255K

3174–12,100

118–566

5.6–13

394

14

540

127–251

84

470

500–1000

 

 E255V

6111–8953

430–725

6.3–11

230.1

36

1400

850

    

C-helix

 D276G

1147

35.3

2.6

25

1.05

       

 E279K

1872

36.5–75

3

39.7

1.5

      

ATP-binding region

 V299L

540–814

23.7

15.8–18

1086

0.3

 

72

200

 

500–1000

  

 F311L

480–1300

23

1.3

   

140

    

 T315I

> 6400–> 20,000

697–> 10,000

137–> 1000

1890

11

> 10,000

13–200

30–74

120

140

3300 (1 μM)

300 (1 μM)

 T315A

125

27–67.5

760

249.6

1.6

 

19–64

88

    

 F317L

810–7500

39.2–91

7.4–18

100.7

1.1

760

36–280

84

 

500–1000

 

 F317V

500

350

17–38

478.4

10

 

223

    

Catalytic segment

 M351T

880–4900

7.8–38

1.1–1.6

29.1

1.5

150

14–86

65

510

250–500

  

 F359V

1400–1825

91–175

2.2–2.7

38.6

10

1300

138–350

    

 V379I

1000–1630

51

0.8

        

Activation loop

 L384M

674–2800

39–41.2

4

19.5

1.1

       

 L387M

1000–1100

49

2

        

 H396R

1750–5400

41–55

1.3–3

33.7

2.95

 

290

    

 H396P

850–4300

41–43

0.6–2

18.1

1.1

95

66–81

160

   

C-term

 F486S

2728–9100

32.8–87

5.6

96.1

1.05

470

   

500

  
 

cKit (CD117)

 
 

 WT

100–150

14.7

79

6313

12.5

840

424–538

  

> 1000

  

 D816V

3800

500

37

2772

72–143

3800

 

100

   

 V560G

75

108

585

181

165

51

 

> 2000

   

 V559D

3927

297

432

 

11

    

250–500

 
 

PDGFR α

 
 

 WT

100

3–71

13–16

> 10,000

1.1

56

60–80

     

 T674I

> 5000

376

> 500

 

9

    

6.25

 

 D842V

642

1310

62

 

154

1281

   

1000

 

 V561D

10

10

   

59

   

> 1000

 
 

PDGFR β

 
 

 WT

39

60.11

4

> 10,000

 

> 1000

103–123

  

< 100

  

 T681I

> 25,000

        

> 1000

 

Aurora

A, B, C

      

> 5000

4–27

13–79

  

Src

> 10,000

 

0.8

1.2

2.2

1700

34

    

Lyn

352

1281

   

19

29

    

References

[20, 69,70,71,72]

[20, 69, 71, 73,74,75]

[69, 76,77,78]

[69, 79, 80]

[69, 79, 81, 82]

[36, 70, 83]

[39, 40, 84]

[40, 85]

[48, 86]

[50]

[53]

[87]

  1. Here, IC50 values related to cell growth assays of tyrosine kinase inhibitors (TKIs) against their main targets, both unmutated (WT) and mutated, are shown in nanomolar units. Regarding Abl kinase, domains harboring specific mutations are displayed on the left of the table. Range values represent either intra- or inter-study variability, while the missing ones are still unavailable to the best of our knowledge, representing putative objectives to be determined in future studies. The activity spectrum of the newest inhibitors, namely rebastinib, tozasertib, danusertib, HG-7-85-01, and GNF, should be characterized in further details to fill the current data gap