Dual FLT3/TOPK inhibitor with activity against FLT3-ITD secondary mutations potently inhibits acute myeloid leukemia cell lines. (13th February 2018)

• Record Type: Journal Article
• Authors: Dayal, Neetu; Opoku-Temeng, Clement; Hernandez, Delmis E; Sooreshjani, Moloud Aflaki; Carter-Cooper, Brandon A; Lapidus, Rena G; Sintim, Herman O
• Is Part Of: Future medicinal chemistry. Volume 10:Number 7(2018)
• Page Start: 823
• Page End: 835
• Publication Date: 2018-02-13
• Subjects: acute myeloid leukemia -- drug resistance -- FLT3-ITD -- secondary mutations -- TOPK; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2017-0298
• Languages: English
• ISSNs: 1756-8919

Abstract

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.