Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice
Name:
Publisher version
View Source
Access full-text PDFOpen Access
View Source
Check access options
Check access options
Date
2019Journal
EBioMedicinePublisher
Elsevier B.V.Type
Article
Metadata
Show full item recordAbstract
Background: 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 AuthorsSponsors
Purdue 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.Keyword
Acute myeloid leukemiaAnti-leukemic effect
FLT3 kinase inhibitors
FLT3-ITD (D835Y/F691L) inhibition
Src kinase inhibitors
Identifier to cite or link to this item
https://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/10713/8663ae974a485f413a2113503eed53cd6c53
10.1016/j.ebiom.2019.01.012
Scopus Count
Collections
Related articles
- Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors, potently inhibit proliferation of acute myeloid leukemia cell lines.
- Authors: Larocque E, Naganna N, Ma X, Opoku-Temeng C, Carter-Cooper B, Chopra G, Lapidus RG, Sintim HO
- Issue date: 2017 Jul
- Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.
- Authors: Moore AS, Faisal A, Gonzalez de Castro D, Bavetsias V, Sun C, Atrash B, Valenti M, de Haven Brandon A, Avery S, Mair D, Mirabella F, Swansbury J, Pearson AD, Workman P, Blagg J, Raynaud FI, Eccles SA, Linardopoulos S
- Issue date: 2012 Jul
- A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with <i>FLT3</i> mutations.
- Authors: Yamaura T, Nakatani T, Uda K, Ogura H, Shin W, Kurokawa N, Saito K, Fujikawa N, Date T, Takasaki M, Terada D, Hirai A, Akashi A, Chen F, Adachi Y, Ishikawa Y, Hayakawa F, Hagiwara S, Naoe T, Kiyoi H
- Issue date: 2018 Jan 25
- Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases.
- Authors: Baska F, Sipos A, Őrfi Z, Nemes Z, Dobos J, Szántai-Kis C, Szabó E, Szénási G, Dézsi L, Hamar P, Cserepes MT, Tóvári J, Garamvölgyi R, Krekó M, Őrfi L
- Issue date: 2019 Dec 15
- Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies.
- Authors: Zhang W, Gao C, Konopleva M, Chen Y, Jacamo RO, Borthakur G, Cortes JE, Ravandi F, Ramachandran A, Andreeff M
- Issue date: 2014 May 1