Deregulation of kinase activity has emerged as a major mechanism by which cancer cells escape from normal physiological constraints over growth and survival. To date, seven kinase inhibitors have received FDA approval and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases implicated in cancer, infectious disease, immunology, and metabolic disorders. However drug resistance has become a major impediment to the continued success of kinase-directed drugs. For example, treatment of patients suffering from advanced Chronic Myeloid Leukemia (CML) with imatinib, an ATP-site directed inhibitor of the Bcr-abl kinase, typically results in the rapid emergence of resistance primarily as a result of Bcr-abl mutations that block the inhibitory activity of the drug. A detailed investigation of the resistant Bcr-abl mutants has identified one amino acid - the so called """"""""gatekeeper"""""""" amino acid - that induces resistance to imatinib and to second generation inhibitors such as nilotinib and dasatinib. Mutation of this gatekeeper position also appears to be a general theme for resistance to inhibitors of the most promising kinase cancer targets including EGFR, FLT3, PDGFR2, FGFR, and c-Src. Therefore, we urgently need new chemical approaches to discover novel compounds that are capable of inhibiting both wild-type and mutant kinase alleles. Our long-term goal is to develop chemical strategies for selectively inhibiting kinases bearing mutations to the gatekeeper residue. Since kinases typically exist in an inactive state and require structural rearrangements to activate their enzymatic activity, we have hypothesized that compounds that prevent this activation might provide a strategy for selectively inhibiting kinases, including those resistant to traditional ATP-competitive inhibitors due to mutations at the gatekeeper residue. Recently we developed a general chemical approach for making potent cellular inhibitors of kinase activation using a scaffold hybridization strategy. Using this approach we discovered three new classes of kinase inhibitors, exemplified by the pyrido[2,3-d]pyrimidin-7-ones 12 &22, pyrimidine naphthylcarboxamide 15, and pyrrolopyridine 24 (Figures 6 &9) that are among the first compounds demonstrated to be capable of potently inhibiting both wild-type and mutant T315I Bcr-abl-dependent cellular proliferation. In this application we propose to test the hypothesis that these inhibitors exert their activity by directly targeting both wild-type and T315I Bcr-abl kinase activity by performing a selection to identify Bcr-abl mutants that are resistant to the compounds. In addition, we propose to use directed medicinal chemistry in conjunction with structural analysis against both wild-type and T315I Bcr-abl to prepare new analogs with improved potency and selectivity. We intend to validate the new approach of optimizing inhibitors that are designed to be capable of simultaneously inhibiting both wild-type and mutant kinases versus the conventional approach of first developing inhibitors of wild-type kinases and then subsequently trying to discover compounds that can inhibit mutant alleles.
Deregulation of protein kinase activity is a common event in the development of cancer. Successful new drugs have been developed by making inhibitors of protein kinases but drug resistance often becomes a problem. Here we propose to develop a new chemical strategy to make inhibitors of drug-resistant protein kinases. These new inhibitors will provide starting points the development of new anti-cancer drugs.
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