The BCR-ABL inhibitor Imatinib is the exemplar of targeted therapy in CML.  Although most patients attain a durable complete cytogenetic response, minimal residual disease persists in nearly all patients.  Importantly, discontinuation of imatinib due to intolerance or resistance is necessary in up to 30% of patients within the first five years of therapy.  Resistance to imatinib usually involves point mutations in the kinase domain of BCR-ABL that impair inhibitor binding.  To address these mutations, second-generation inhibitors nilotinib and dasatinib were developed leading to recaptured response.  Despite the effectiveness of these newer agents which successfully target most imatininb failures, pockets of resistance remain and neither compound inhibits the T315I gatekeeper mutant which constitutes 15-20% of all clinically observed mutants.  More recently, several next-generation inhibitors including DCC-2036, ponatinib (AP24534) and others have emerged that effectively target T315I and other disease resistant mutations.  Critical to the evolution of these next generation inhibitors has been the judicious use of structure to guide design of molecules which either avoid or proactively engage the increased bulk of the isoleucine mutation resulting in potent gatekeeper inhibition.  Finally, ponatinib has been shown to abrogate resistance in a cell-based mutagenesis screen revealing no liabilities and suggesting that final-generation inhibitors of BCR-ABL driven CML may become a reality.

Targeting Imatinib resistance: Progress toward “final generation” inhibitors of BCR-ABL for the treatment of CML

244th National Meeting (2012)

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