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 | Â | Â | Â | 19 | 29 | Â | Â | Â | Â | ||
References | [50] | [53] | [87] |