Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice
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AbstractBackground: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to <10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD). Inhibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but patients often relapse due to secondary mutations in the FLT3 TKD, like D835Y and F691 L mutations. Methods: Alkynyl aminoisoquinoline and naphthyridine compounds were synthesized via Sonogashira coupling. The compounds were evaluated for their in vitro and in vivo effects on leukemia growth. Findings: The compounds inhibited FLT3 kinase activity at low nanomolar concentrations. The lead compound, HSN431, also inhibited Src kinase activity. The compounds potently inhibited the viability of MV4-11 and MOLM-14 AML cells with IC50 values <1 nM. Furthermore, the viability of drug-resistant AML cells harboring the D835Y and F691 L mutations were potently inhibited. In vivo efficacy studies in mice demonstrated that the compounds could drastically reduce AML proliferation in mice. Interpretation: Compounds that inhibit FLT3 and downstream targets like Src (for example HSN431) are good leads for development as anti-AML agents. Fund: Purdue University, Purdue Institute for Drug Discovery (PIDD), Purdue University Center for Cancer Research, Elks Foundation and NIH P30 CA023168. © 2019 The Authors
SponsorsPurdue University, Purdue Institute for Drug Discovery (PIDD), Purdue University Center for Cancer Research and Elks Foundation provided funding. NMR and MS data were acquired by the NMR and MS facilities supported by NIH P30 CA023168. Herman Sintim (corresponding author) had full access to all the data in the study and had final responsibility for the decision to submit for publication. The funders had no roles in study design, data collection, analysis, interpretation or writing the manuscript.
KeywordAcute myeloid leukemia
FLT3 kinase inhibitors
FLT3-ITD (D835Y/F691L) inhibition
Src kinase inhibitors
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85060455047&doi=10.1016%2fj.ebiom.2019.01.012&partnerID=40&md5=a6684ebbb50e1ef08959552c89cc8507; http://hdl.handle.net/10713/8663
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