AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance

被引：964

作者：

O'Hare, Thomas ^{[1
,2
]}

Shakespeare, William C. ^{[3
]}

Zhu, Xiaotian ^{[3
]}

Eide, Christopher A. ^{[1
,2
]}

Rivera, Victor M. ^{[3
]}

Wang, Frank ^{[3
]}

Adrian, Lauren T. ^{[1
,2
]}

Zhou, Tianjun ^{[3
]}

Huang, Wei-Sheng ^{[3
]}

Xu, Qihong ^{[3
]}

Metcalf, Chester A., III ^{[3
]}

Tyner, Jeffrey W. ^{[1
]}

Loriaux, Marc M. ^{[1
]}

Corbin, Amie S. ^{[1
,2
]}

Wardwell, Scott ^{[3
]}

Ning, Yaoyu ^{[3
]}

Keats, Jeffrey A. ^{[3
]}

Wang, Yihan ^{[3
]}

Sundaramoorthi, Raji ^{[3
]}

Thomas, Mathew ^{[3
]}

Zhou, Dong ^{[3
]}

Snodgrass, Joseph ^{[3
]}

Commodore, Lois ^{[3
]}

Sawyer, Tomi K. ^{[3
]}

Dalgarno, David C. ^{[3
]}

Deininger, Michael W. N. ^{[1
]}

Druker, Brian J. ^{[1
,2
]}

Clackson, Tim ^{[3
]}

机构：

[1] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Knight Canc Inst, Portland, OR 97239 USA

[2] Howard Hughes Med Inst, Portland, OR 97239 USA

[3] ARIAD Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

CANCER CELL | 2009年 / 16卷 / 05期

关键词：

KINASE DOMAIN MUTATIONS; CHRONIC MYELOGENOUS LEUKEMIA; DASATINIB BMS-354825; IMATINIB RESISTANCE; NILOTINIB; CML; AMN107; MESYLATE;

D O I：

10.1016/j.ccr.2009.09.028

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：401 / 412

页数：12

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