Targeting AML-associated FLT3 mutations with a type I kinase inhibitor
LaQuita M. Jones, Katelyn Melgar, Lyndsey Bolanos, Kathleen Hueneman, Morgan M. Walker, Jian-Kang Jiang, Kelli M. Wilson, Xiaohu Zhang, Jian Shen, Fan Jiang, Patrick Sutter, Amy Wang, Xin Xu, Gregory J. Tawa, Scott B. Hoyt, Mark Wunderlich, Eric O’Brien, John P. Perentesis, Daniel T. Starczynowski, Craig J. Thomas
LaQuita M. Jones, Katelyn Melgar, Lyndsey Bolanos, Kathleen Hueneman, Morgan M. Walker, Jian-Kang Jiang, Kelli M. Wilson, Xiaohu Zhang, Jian Shen, Fan Jiang, Patrick Sutter, Amy Wang, Xin Xu, Gregory J. Tawa, Scott B. Hoyt, Mark Wunderlich, Eric O’Brien, John P. Perentesis, Daniel T. Starczynowski, Craig J. Thomas
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Concise Communication Hematology Oncology

Targeting AML-associated FLT3 mutations with a type I kinase inhibitor

Abstract

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.

Authors

LaQuita M. Jones, Katelyn Melgar, Lyndsey Bolanos, Kathleen Hueneman, Morgan M. Walker, Jian-Kang Jiang, Kelli M. Wilson, Xiaohu Zhang, Jian Shen, Fan Jiang, Patrick Sutter, Amy Wang, Xin Xu, Gregory J. Tawa, Scott B. Hoyt, Mark Wunderlich, Eric O’Brien, John P. Perentesis, Daniel T. Starczynowski, Craig J. Thomas

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Figure 3

NCGC1481 targets clinically relevant FLT3-mutant AML cells in vivo.

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NCGC1481 targets clinically relevant FLT3-mutant AML cells in vivo. (A) ...
(A) Experimental design of the xenograft studies. (B) After treatment with NCGC1481, MOLM14-FLT3-ITD(D835Y) cells (human CD33+ [hCD33+]) were isolated from the BM for immunoblot analysis. (C) BM aspirates were analyzed for leukemic burden on day 31 after transplantation (n = 5 mice per condition). Values are expressed as the mean ± SEM for individual mice. P = 0.06 for PBS versus NCGC1481; P = 0.03 for AC220 versus NCGC1481; Dunn’s multiple comparisons test. (D) Leukemia-free survival of NSG mice xenografted with MOLM14-FLT3-ITD(D835Y) cells and treated with the indicated FLT3i or vehicle (n = 5 mice per group). *P < 0.05, by log-rank (Mantel-Cox) test. (E) Experimental design of patient-derived xenograft studies. (F) BM was analyzed for leukemic burden around day 65 after transplantation (n = 5–7 mice per condition). Values are expressed relative to baseline values on day 28 for individual mice. (G) Leukemia-free survival of NSGS mice xenografted with AML-5 cells and treated with the indicated FLT3i or vehicle (n = 7–8 mice per group). ****P < 0.0001, by log-rank (Mantel-Cox) test.