MEDI 357 |
| Imatinib, a BCR-ABL kinase inhibitor, is the standard of care for patients with chronic myelogenous leukemia. Mutations in the ABL kinase domain of the BCR-ABL protein result in interference with imatinib binding. Resistance to imatinib treatment leads to 50-90% of relapses of the disease. The T315I mutation accounts for 10-20 % of all observed mutations and is resistant to all approved and clinically advanced kinase inhibitors. TargeGen has designed and synthesized a new series of compounds based on a pyrimidine template by exploiting a unique binding interaction with Glu286 of the αC helix deep within the hydrophobic pocket. Optimization efforts guided by molecular modeling resulted in compounds with low nM ABL and ABL-T315I activity. Here we present the design and SAR of inhibitors with low nM activity against the ABL-T315I. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |