AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance
AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance
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DOI：
10.1016/j.ccr.2009.09.028
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发表时间：
2009-11-03
期刊：
影响因子：
50.3
通讯作者：
Clackson, Tim
中科院分区：
文献类型：
--
作者：
O'Hare, Thomas;Shakespeare, William C.;Clackson, Tim
伊马替尼对BCR-ABL的抑制作用在许多慢性粒细胞白血病（CML）患者中诱导了持久的缓解，但激酶结构域突变引起的耐药可能导致复发，并转换为尼洛替尼或达沙替尼的二线治疗。尽管有三种获批的治疗方案，交叉耐药BCR-ABL ABL（T315 I）突变和序贯抑制剂治疗中选择的化合物突变体仍然是主要的临床挑战。我们报告了AP 24534的设计和临床前评价，AP 24534是一种有效的口服多靶点激酶抑制剂，对T315 I和其他BCR-ABL突变体具有活性。在细胞和生化试验中，AP 24534可抑制所有检测的BCR-ABL突变体，抑制小鼠中BCR-ABL（T315 I）驱动的肿瘤生长，并在基于细胞的诱变筛选中完全消除耐药性。我们的工作支持AP 24534作为泛BCR-ABL抑制剂治疗CML的临床评价。
Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.