Abstract
Bcr-Abl, a fusion oncogenic protein with deregulated tyrosine kinase activity, is the pathophysiological cause of chronic myeloid leukemia (CML). Current treatment of CML with tyrosine kinase inhibitor drugs like Imatinib (Gleevec, Novartis) is not always effective since some of the downstream signaling pathways of Bcr-Abl are kinase-independent. This problem can potentially be resolved if elimination, instead of inhibition, of Bcr-Abl could be achieved. The Hedstrom Laboratory recently discovered that proteins tagged with the hydrophobic molecule, Triboc-Arginine (Boc3Arg), are degraded by the proteasome. In order to evaluate the efficacy of Boc3Arg tag as a degron of Bcr-Abl, we designed an inhibitor, AS-22, by linking Boc3Arg to GNF-2, which belongs to a new class of allosteric inhibitors of Bcr-Abl. Protein degradation assays were performed with the lysate of BaF3.p210 cells which express Bcr-Abl. Analysis of one set of assays showed that a 60 min incubation of BaF3.p210 lysate with GNF-2 brought about a 25±13 % (N=2) reduction in the amount of Bcr-Abl present whereas the percentage of reduction shown by AS-22 was 73±11% (N=5). However, replication of the results is required to verify the potency of AS-22 and gauge the utility of the Boc3Arg tag as a degron of Bcr-Abl. If successful, this project may not only contribute towards finding a better drug for CML, but also serve as an alternate model for cancer therapy.