1. Gleevec vs. BMS-354825 Druker vs. Sawyers
Yashar Kalani
Biochemistry 230

2. Imatinib or Gleevec inhibitor of BCR-ABL tyrosine kinase.
Binds to the ATP binding site of BCR-ABL only when the activation loop is closed and thus stabilizes the protein in an inactive conformation.
In addition, the normally smooth contour of the phosphate binding loop of ABL is distorted by Gleevec binding.
Produces clinical remission in chronic myeloid leukemia (CML) with minimal toxicity.

3. To date 17 mutations, mostly within the kinase domain of BCR-ABL have been observed.
Most resistant form
Most frequently seen (20%)
Majority impair the ability of the kinase to adopt specific closed conformation to which Gleevec binds and some inhibit drug binding directly.

4. A family of SRC-ABL inhibitors also bind to the ATP-binding site in ABL, but without regard for the position of the activation loop; this highlights their potential use as therapeutics.

5. Inhibitor of SRC-family kinases.
Competitive ATP inhibitor with broad spectrum antiproliferative activity against hematological and solid tumor cell lines.
Based on structural insight from other dual SRC-ABL inhibitors, BMS was reasoned to impose less stringent conformational requirements on ABL for kinase inhibition.

6. BMS was more potent than Gleevec at inhibiting nonmutated BCR-ABL kinase activity in a cell-based assay.

7. T315I Only resistant form
Activity of 14 of 15 relevant resistant forms was inhibited in the low nanomolar range.

8. Growth of Ba/F3 cells expression various isoforms was also inhibited.

9. To assess its potential as a therapeutic, a SCID mouse model of Gleevec resistance was used.
Mice injected with Ba/F3 cells expressing different mutants (tagged with luciferase gene).

10. WT and mutant forms appeared healthy with no evidence of weight loss, lethargy or ruffled fur and showed greater than one log lower levels of bioluminescent activity two weeks after therapy.

11. Conclusions
The primary consequence of all ABL kinase domain mutations associated with Gleevec resistance is the impairment of kinase domain flexibility such that the kinase domain is unable to assume the optimal inactive conformation needed for Gleevac binding.
Inhibitors with less stringent conformational requirement for binding are predicted to retain activity against mutant forms.
All material is derived from Shah et al. Science, 305, (2004).