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AP24163 Inhibits the Gatekeeper Mutant of BCR‐ABL and Suppresses In vitro Resistance
Author(s) -
Azam Mohammad,
Powers John T.,
Einhorn William,
Huang WeiSheng,
Shakespeare William C.,
Zhu Xiaotian,
Dalgarno David,
Clackson Tim,
Sawyer Tomi K.,
Daley George Q.
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00911.x
Subject(s) - nilotinib , dasatinib , mutant , chronic myelogenous leukemia , protein kinase domain , imatinib , mutation , abl , in vitro , chemistry , kinase , drug resistance , biology , cancer research , pharmacology , tyrosine kinase , biochemistry , leukemia , genetics , signal transduction , myeloid leukemia , gene
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most imatinib resistance variants, but are ineffective against the gatekeeper mutant, T315I. Gatekeeper mutation activates the kinase by stabilizing the hydrophobic spine. Here, we describe that the rationally designed compound AP24163 can inhibit native and gatekeeper mutants of the BCR/ABL kinase. Structural modelling suggests that AP24163 affects the flexibility of the P‐loop and destabilizes the active conformation by disrupting the hydrophobic spine. In vitro screening for drug resistance identified clones with compound mutations involving both the P‐loop and T315I. Our studies provide structural insights for the design of inhibitors against the gatekeeper mutant and suggest that up‐front combination therapy may be required to prevent the emergence of compound‐resistant mutations.