IC50 values of BCR-ABL mutations observed in patients resistant to IM
. | Imatinib IC50, nM . | . | |
|---|---|---|---|
| BCR-ABL . | Biochemical . | Cellular . | |
| Wild type | 300 | 260-500 | |
| M244V | 380 | 2 000 | |
| P-loop | |||
| L248V | NA | 1 500 | |
| G250E | 1 000 | 1 350-3 900 | |
| Q252H | NA | 1 200-2 800 | |
| Y253F | > 5 000 | 3 475 | |
| Y253H* | > 5 000 | > 10 000 | |
| E255K | 2 800 | 4 400-8 400 | |
| E255V | > 5 000 | > 5 000 | |
| D276G | NA | 1 500 | |
| T277A | NA | NA | |
| F311L | 775 | 480 | |
| F311I | NA | NA | |
| T315I* | > 5 000 | > 10 000 | |
| F317L* | 900 | 810-1 500 | |
| M343T | NA | NA | |
| Catalytic domain | |||
| M351T | 820 | 930 | |
| M351V | NA | NA | |
| E355D | NA | NA | |
| E355G | NA | 400 | |
| F359V* | 4 700 | 1 200 | |
| Activation loop | |||
| V379I | 800 | 1 630 | |
| A380T* | 340 | 2 450 | |
| F382L | NA | NA | |
| L387M | 1 500 | 1 000 | |
| L387F | NA | 1 100 | |
| H396P | 340-800 | 850-4 200 | |
| H396R | 1 950 | 1 750 | |
| S417Y | NA | NA | |
| E459K | NA | NA | |
| F486S | 1 230 | 2 800 | |
. | Imatinib IC50, nM . | . | |
|---|---|---|---|
| BCR-ABL . | Biochemical . | Cellular . | |
| Wild type | 300 | 260-500 | |
| M244V | 380 | 2 000 | |
| P-loop | |||
| L248V | NA | 1 500 | |
| G250E | 1 000 | 1 350-3 900 | |
| Q252H | NA | 1 200-2 800 | |
| Y253F | > 5 000 | 3 475 | |
| Y253H* | > 5 000 | > 10 000 | |
| E255K | 2 800 | 4 400-8 400 | |
| E255V | > 5 000 | > 5 000 | |
| D276G | NA | 1 500 | |
| T277A | NA | NA | |
| F311L | 775 | 480 | |
| F311I | NA | NA | |
| T315I* | > 5 000 | > 10 000 | |
| F317L* | 900 | 810-1 500 | |
| M343T | NA | NA | |
| Catalytic domain | |||
| M351T | 820 | 930 | |
| M351V | NA | NA | |
| E355D | NA | NA | |
| E355G | NA | 400 | |
| F359V* | 4 700 | 1 200 | |
| Activation loop | |||
| V379I | 800 | 1 630 | |
| A380T* | 340 | 2 450 | |
| F382L | NA | NA | |
| L387M | 1 500 | 1 000 | |
| L387F | NA | 1 100 | |
| H396P | 340-800 | 850-4 200 | |
| H396R | 1 950 | 1 750 | |
| S417Y | NA | NA | |
| E459K | NA | NA | |
| F486S | 1 230 | 2 800 | |
Other mutations not yet detected in patients were recovered from in vitro saturation mutagenesis screenings for mutations conferring resistance to IM or other TK inhibitors. They include M237I, G250A, G250V, E255D, A269V, E281K, E282D, K285N, V289S, V299L, T315A, F317C, V338G, Q346H, S348L, M451L, E352K, E355A, A366D, G398R, G463D, M472I, and E494A, with a cellular IC50 of less than 1460 nM (that is, the mean trough plasma level of IM in patients treated with 400 mg daily); and E255R, E275K, M278L, E279K, E281K, E292Q, Q300H, F311V, T315S, E316D, G321W, D325N, A380S, L384M, M388L, E450K, and E499K, with a cellular IC50 greater than 1460 nM. Data reviewed in Martinelli et al.154
IC50 indicates the concentration that inhibits by 50% the biochemical TK activity of BCR-ABL and suppresses by 50% the growth of Ph+ cell lines; NA, not available.
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