AP24163 Inhibits the Gatekeeper Mutant of BCR-ABL and Suppresses In vitro Resistance
AP24163 Inhibits the Gatekeeper Mutant of BCR-ABL and Suppresses In vitro Resistance
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DOI：
10.1111/j.1747-0285.2009.00911.x
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发表时间：
2010-02-01
影响因子：
3
通讯作者：
Daley, George Q.
中科院分区：
文献类型：
--
作者：
Azam, Mohammad;Powers, John T.;Daley, George Q.
ABL激酶结构域突变是慢性粒细胞白血病患者对伊马替尼耐药的主要机制。第二代bcr/abl抑制剂尼洛替尼和达沙替尼有效地抑制了大多数伊马替尼耐药变异体，但对看门人突变体T315I无效。看门人突变通过稳定疏水脊椎来激活激酶。在这里，我们描述了合理设计的化合物AP24163可以抑制BCR/ABL激酶的天然和守门人突变体。结构模拟表明，AP24163影响P-环的灵活性，并通过破坏疏水脊柱来破坏活性构象的稳定。体外耐药筛选鉴定出同时涉及P-loop和T315I的复合突变克隆。我们的研究为针对看门人突变的抑制剂的设计提供了结构上的见解，并表明可能需要预先联合治疗来防止复合耐药突变的出现。
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.