Despite tremendous clinical success of imatinib, mutation in the kinase domain of Bcr-Abl has become a major mechanism of acquired drug resistance.In order to overcome various mutations including the T315I gate-keeper residue mutation, we have designed and synthesized a series of chemical compounds which bind to Abl in the DFG in and out binding modes.Active compounds against both wild type and the T315I mutant Abl were identified.Further optimization has led to AP24534, an oral, multi-targeted kinase inhibitor, which is currently being investigated in Phase 1 clinical trial in patients with drug-resistant and refractory hematological malignancies, including chronic myeloid leukemia(CML).