Beyond the Gatekeeper: Imatinib- and Dasatinib-Resistant BCR-ABL/F317 Mutations Confer Cross-Resistance to VX-680 but Are Sensitive to a Structural Derivative of VX-680

摘要: The management of chronic phase CML has been revolutionized by selective ABL tyrosine kinase inhibitor (TKI) therapy. Despite the effectiveness these targeted agents, long-term control blast and Ph+ ALL elusive, where majority patients relapse within 6–12 months. For ALL, two TKIs are currently approved: imatinib dasatinib. While head-to-head comparisons agents have not performed, it is generally believed that dasatinib more active agent for phases disease. In most cases, loss response to driven BCR-ABL domain mutations. than 70 mutations associated with clinical resistance imatinib, appears vulnerable primarily five mutations: V299L, T315A, T315I, F317I, F317L. Of these, T315I F317L cross-resistant imatinib. achievement remissions in a combination can collectively suppress all resistant holds therapeutic promise. BCR-ABL/T315I mutation, which confers high degree approved TKIs, referred as “molecular gatekeeper”, restricts access deeper hydrophobic pocket makes an important stabilizing H-bond nilotinib. Aurora VX-680 was first compound activity against vitro, well clinically. To determine promise VX-680, we assessed dasatinib-resistant using cell-based flow cytometric assay activity. three mutants sensitive, at F317 demonstrated resistance. We tested number other inhibitors different chemotypes found each had similar difficulty inhibiting BCR-ABL/F317 mutants. Based upon co-crystal structure complexed ABL, performed structure-activity relationship studies 12 scaffold derivatives, successfully identified structural modifications increase inhibitory Moreover, one derivatives increases selectivity relative kinases, may help reduce likelihood suppressing normal hematopoiesis, dose-limiting toxicity substantially limit their hematologic malignancies such ALL. Lastly, ABL/F317 select effort understand how confer broad range inhibitors. Interestingly, recent study reported successful selection inhibitor-resistant clones derived from human colon cancer cell line (Girdler et al, 2008). no resistance-conferring were isolated L154, gatekeeper residue, detected Y156 B, corresponds ABL. B inhibitors, including VX-680. As being studied variety non-hematologic malignancies, there increasing need overcome mechanisms whereby this residue agents. It hoped our will lead only development effective adjunctive treatment but also shed light on growing problem conferred residues correspond kinases.