Table 2.
Biochemical activities of the DSA compounds against clinically-relevant, imatinib-resistant Abl mutants and the corresponding c-Src mutants.
| IC50 (nM) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Abl wt | Abl Y253H | Abl E255V | Abl 359V | Abl T315I* | Src wt | Src F278H | Src E280V | Src F382V | Src T338I | |
| DSA1 | 10 ± 3 | 25 ± 8 | 40 ± 5 | 27 ± 1 | 64 ± 5 | 4.6 ± 1.5 | 14 ± 2 | 6.5 ± 0.8 | 13 ± 5 | 6.4 ± 1.2 |
| DSA2 | 14 ± 3 | N/D | N/D | N/D | 71 ± 3 | 4.6 ± 0.9 | N/D | N/D | N/D | 11 ± 2 |
| DSA3 | 2.9 ± 0.5 | N/D | N/D | N/D | 11 ± 1 | < 1 | N/D | N/D | N/D | 4.7 ± 1.0 |
| DSA4 | 18 ± 3 | N/D | N/D | N/D | 45 ± 9 | 6.4 ± 2.2 | N/D | N/D | N/D | 15 ± 1 |
| DSA5 | 7.2 ± 1.3 | N/D | N/D | N/D | 17 ± 3 | 3.4 ± 1.0 | N/D | N/D | N/D | 5.3 ± 1.0 |
| DSA6 | 7.6 ± 1.4 | N/D | N/D | N/D | 45 ± 2 | 3.0 ± 0.6 | N/D | N/D | N/D | 9.6 ± 1.0 |
| DSA7 | 1.5 ± 0.2 | 2.3 ± 0.2 | 3.8 ± 0.8 | 3.7 ± 0.4 | 6.3 ± 0.7 | < 1 | 1.7 ± 0.1 | 1.3 ± 0.4 | 2.1 ± 0.7 | 2.6 ± 0.5 |
| DSA8 | 2.7 ± 0.5 | 3.5 ± 0.1 | 9.5 ± 3.8 | 3.8 ± 0.8 | 33 ± 3 | 2.8 ± 0.3 | 7.0 ± 2.0 | 4.0 ± 1.2 | 4.4 ± 1.7 | 18 ± 6 |
| DSA9 | 7.7 ± 5.3 | N/D | N/D | N/D | 92 ± 35 | 8.3 ± 4.2 | N/D | N/D | N/D | 13 ± 5 |
| imatinib | 11 ± 3 | 310 ± 30 | 76 ± 10 | 32 ± 2 | >10000 | >10000 | >10000 | >10000 | >10000 | >10000 |
Full length Abl Thr315Ile was obtained from a commercial source (Invitrogen) whereas the other proteins are kinase domain constructs expressed and purified from bacteria. N/D = not determined. All activity assays were performed in triplicate or quadruplicate.