Acquired resistance to the ABL tyrosine kinase inhibitor (TKI) imatinib is a significant clinical problem for patients with chronic myeloid leukemia (CML), where a major resistance mechanism is mutations in the ABL kinase domain that render the BCR-ABL enzyme insensitive to the drug. The gatekeeper mutation Thr 315 Ile (T315I) arises at high frequency in patients relapsing after sequential therapy with second-line TKIs such as dasatinib or nilotinib (

Shah et al., J Clin Invest 2007;117:2562
), and confers pan-resistance to all ATP-competitive TKIs. Using structure-based rational drug design, we have developed a novel chemical class of compounds that bind to five distinct structural pockets that the ABL kinase uses to switch between the inactive and active conformations. Diversity in these “switch pockets” between kinases can be exploited to fine-tune the selectivity of an inhibitor against the rest of the kinome. Two development candidate ABL inhibitors have emerged from this effort: DCC-2036 and DCC-2157. Both compounds potently (IC50 = 0.8–4.0 nM) inhibit purified ABL in the switch-off (unphosphorylated) and switch-on (phosphorylated) states via a non-ATP-competitive mechanism, and avoid steric clash with Ile 315. Both drugs also impair proliferation and induce apoptosis of Ba/F3 cells expressing a wide variety of BCR-ABL TKI-resistant mutants, including T315I, many P-loop mutants, and the dasatinib-resistant mutant F317L. DCC-2036 is highly selective for ABL, FLT3, TIE2, and Src family kinases, and when dosed at 100 mg/kg/day by oral gavage, significantly prolonged the survival of mice with CML-like myeloproliferative disease induced by retroviral expression of BCR-ABL WT and T315I in bone marrow. Genetic studies in mice (
Hu et al., Nat Genet 2004;36:453
) suggest that the Src inhibitory activity of DCC-2036 would be beneficial against Ph+ B-cell acute lymphoblastic leukemia (B-ALL), and indeed DCC-2036 was superior to dasatinib (
Hu et al., PNAS 2006;103:16870
) in prolonging survival of mice with B-ALL induced by BCR-ABL T315I. By contrast, DCC-2157 is selective for ABL, KIT, and PDGFRA/B kinases, and pharmacodynamic studies demonstrated prolonged (>18 hour) inhibition of phospho-Stat5 in BCR-ABL+ leukemic cells following a single oral 100 mg/kg dose. Treatment of mice with CML-like disease induced by BCR-ABL T315I with DCC-2157 at 50 mg/kg every other day induced virtually complete suppression of leukemia and extensive prolongation of survival. These results demonstrate that switch pocket drug design technology yields ABL TKIs with distinct pharmacologic profiles that are promising new weapons for the treatment of de novo and drug-resistant Ph+ leukemias.

Topics:
bcr-abl tyrosine kinase, burkitt's lymphoma, leukemia, mice, proto-oncogene proteins c-abl, protein-tyrosine kinase inhibitor, phosphotransferases, dasatinib, leukemia, b-cell, acute, enzymes

Disclosures: Van Etten:Deciphera Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wise:Deciphera Pharmaceuticals: Employment, Equity Ownership. Petillo:Deciphera Pharmaceuticals: Employment, Equity Ownership. Flynn:Deciphera Pharmaceuticals: Employment, Equity Ownership.

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2008, The American Society of Hematology
2008
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