MEDI 359 |
| Although Gleevec has been a remarkable success for treatment of CML, a significant number of patients develop drug resistance. It is estimated that 50-90% of resistance is drug related and due to mutations that alter the affinity of Gleevec to the mutated enzyme. The T315I (gatekeeper) mutation stands out among the >40 clinically identified mutations because it shows highest prevalence (>20%), and maintains resistance to all recently developed BCR-ABL inhibitors (Tasigna, Sprycel) that target most other mutations. Using molecular modeling, we have developed two series of novel ABL-T315I inhibitors to target the ABL-T315I mutant both in enzyme and cell-based assays. We will present the synthetic strategies that enabled optimizations of nM inhibitors of ABL-T315I in both series. |
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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 |