Show simple item record

dc.contributor.authorNaganna, N.
dc.contributor.authorOpoku-Temeng, C.
dc.contributor.authorChoi, E.Y.
dc.date.accessioned2019-03-29T14:47:34Z
dc.date.available2019-03-29T14:47:34Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85060455047&doi=10.1016%2fj.ebiom.2019.01.012&partnerID=40&md5=a6684ebbb50e1ef08959552c89cc8507
dc.identifier.urihttp://hdl.handle.net/10713/8663
dc.description.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 Authorsen_US
dc.description.sponsorshipPurdue 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.en_US
dc.description.urihttps://dx.doi.org/10.1016/j.ebiom.2019.01.012en_US
dc.language.isoen_USen_US
dc.publisherElsevier B.V.en_US
dc.relation.ispartofEBioMedicine
dc.subjectAcute myeloid leukemiaen_US
dc.subjectAnti-leukemic effecten_US
dc.subjectFLT3 kinase inhibitorsen_US
dc.subjectFLT3-ITD (D835Y/F691L) inhibitionen_US
dc.subjectSrc kinase inhibitorsen_US
dc.titleAmino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in miceen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.ebiom.2019.01.012
dc.identifier.pmid30686755


Files in this item

Thumbnail
Name:
Publisher version

This item appears in the following Collection(s)

Show simple item record