his review will highlight BMS 378806 BMS-806 recent work that has been performed to determine the biochemical mechanisms that protein kinases have developed to gain resistance to smallmolecule inhibitors. These studies provide information on the inherent structural plasticity of the catalytic domain of protein kinases and give insight into how active site mutations can affect ligand binding. While several routes are available for cells to gain resistance to targeted kinase inhibitors, this review will focus on the role of kinase domain mutations that hinder drug binding but preserve catalytic activity. For a more comprehensive overview of kinase drug resistance, the reader is referred to a recent review by Mansour and co workers.
Resistance to Inhibitors of BCR ABL Chronic myelogenous leukemia, which accounts for 15 20% of adult leukemia in Western populations, is a blood and bone marrow disease that is caused by unregulated proliferation of myeloid Avasimibe cells. In a majority of cases, CML coincides with a reciprocal translocation of chromosomes 9 and 22, which is referred to as the Philadelphia chromosome. This chromosomal abnormality results in the generation of a fusion gene, named BCRABL1, from the joining of the breakpoint cluster region gene and the ABL tyrosine kinase Krishnamurty and Maly Page 2 ACS Chem Biol. Author manuscript, available in PMC 2011 January 15. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript gene. The protein product of the BCR ABL1 gene, BCR ABL, is a 210 kDa protein that contains the constitutively active tyrosine kinase domain of ABL fused to 902 or 927 amino acids of BCR.
A large part of the pathogenesis of BCR ABL1 positive leukemia is driven by the increased catalytic activity of the tyrosine kinase ABL, which phosphorylates a number of downstream substrates and results in cell transformation and proliferation. The small molecule kinase inhibitor imatinib has revolutionized the treatment of CML . Imatinib is a 2 phenylaminopyrimidine derivative inhibitor that targets the ATP binding site of ABL. While imatinib was originally designed to target the active conformation of the ATP binding pocket of ABL kinase, it was later discovered that this inhibitor targets the DFG out inactive form . Despite the challenge in identifying kinase inhibitors with high selectivity, a number of in vitro and proteomic screens have demonstrated that imatinib only has submicromolar potency against several other kinases besides BCR ABL.
This high degree of selectivity for inhibiting the kinase catalytic activity that is responsible for driving the pathogenesis of CML is believed to be at least partially responsible for the clinical success of this drug. More than 80% of patients that undergo imatinib treatment in the early stages of CML show a complete cytogenetic response . This response has been found to be robust, with less than 3% of these patients progressing to more advanced stages of CML after five years. However, imatinib therapy is not the equivalent of a cure for CML because residual leukemia cells persist in all patients and the recurrence of active leukemia is common amongst patients that cease treatment. Despite the effectiveness of imatinib as a targeted therapeutic for the treatment of CML, the emergence of clinical resistance is an ongoing challenge. While relapse is infrequent for patients unde