Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 4, Pages 2017-2023Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI127907
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Funding
- Cincinnati Children's Hospital Research Foundation
- Leukemia Lymphoma Society
- Cancer-Free KIDS
- NIH [R35HL135787, RO1DK113639]
- intramural research programs of the National Center for Advancing Translational Sciences
- NCI
- St. Baldrick's Foundation Research Fellowship [524748]
- NIH Research Training and Career Development Grant [F31CA217140]
- NCI grant [R50CA211404]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [ZIATR000369, ZIATR000044, ZICTR000242] Funding Source: NIH RePORTER
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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.
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