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Targeting AML-associated FLT3 mutations with a type I kinase inhibitor
LaQuita M. Jones, … , Daniel T. Starczynowski, Craig J. Thomas
LaQuita M. Jones, … , Daniel T. Starczynowski, Craig J. Thomas
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):2017-2023. https://doi.org/10.1172/JCI127907.
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Concise Communication Hematology Oncology

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

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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 1

Chemical structure and inhibitory function of NCGC1481.

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Chemical structure and inhibitory function of NCGC1481.
(A) Chemical str...
(A) Chemical structure of NCGC1481. (B) A ribbon/surface representation of the cocrystal of NCGC1481-FLT3 (PDB: 6IL3) and a ribbon/surface representation of the cocrystal of AC220-FLT3 (PDB: 4XUF). (C) Detailed view of the Asp835-Ser838 hydrogen bond formed in the cocrystal of NCGC1481-FLT3 relative to loss of this hydrogen bond in the cocrystal of AC220-FLT3 (left 2 panels). Detailed view of the F691-ligand hydrogen bond formed in the cocrystal of NCGC1481-FLT3 and the cocrystal of AC220-FLT3 (right 2 panels). (D) Immunoblotting of isogenic MOLM14-FLT3-ITD cell lines treated with the indicated inhibitors for 90 minutes. (E) Immmunoblotting of MOLM14-FLT3-ITD(D835Y) cell lines treated with the indicated inhibitors for 90 minutes. See complete unedited blots in the supplemental material.

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