Journal
FUTURE MEDICINAL CHEMISTRY
Volume 10, Issue 7, Pages 823-835Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc-2017-0298
Keywords
acute myeloid leukemia; drug resistance; FLT3-ITD; secondary mutations; TOPK
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Funding
- Purdue University, Purdue Cancer Center
- Elks Foundation
- NIH [P30 CA023168]
- NATIONAL CANCER INSTITUTE [P30CA023168] Funding Source: NIH RePORTER
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Aim: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691. Results: HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines. HSD1169 was active against MV4-11 and Molm-14 (FLT3-ITD cell lines) but not NOMO-1 or HL60 (FLT3-WT cell lines). HSD1169 was also active against sorafenib-resistant Molm13-res cell line (containing FLT3-ITD/D835Y). Conclusion: HSD1169 or an analog could become a therapeutic agent for AML containing drug-resistant FLT3-ITD.
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