Evidence map›Paper›PMID 30686755›Full record

ArticleEBioMedicine2019

Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice.

N Naganna, Clement Opoku-Temeng, Eun Yong Choi, Elizabeth Larocque, Elizabeth T Chang, Brandon A Carter-Cooper, Modi Wang, Sandra E Torregrosa-Allen, Bennett D Elzey, Rena G Lapidus and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Continuous Flow Synthesis of Anticancer Drugs.Molecules (Basel, Switzerland) · 2021
    Review
  6. Article
  7. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

N NagannaPurdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Clement Opoku-TemengPurdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Graduate Program in Biochemistry, University of Maryland, College Park, MD 20742, USA.
Eun Yong ChoiUniversity of Maryland School of Medicine, Baltimore, MD, USA.
Elizabeth LarocquePurdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Elizabeth T ChangUniversity of Maryland School of Medicine, Baltimore, MD, USA.
Brandon A Carter-CooperUniversity of Maryland School of Medicine, Baltimore, MD, USA.
Modi WangPurdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Sandra E Torregrosa-AllenPurdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
Bennett D ElzeyPurdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
Rena G LapidusUniversity of Maryland School of Medicine, Baltimore, MD, USA.
Herman O SintimPurdue Institute for Drug Discovery, West Lafayette, IN 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: hsintim@purdue.edu.

Funding

Transgenic Mouse Core Facility Shared Resource (TMCF-SR)P30CA023168 · NCI · PURDUE UNIVERSITY WEST LAFAYETTE · PI Andrea L Kasinski · 1985 to 2026
$43.4M
NCI NIH HHS P30 CA023168
6 · The paper itself

Abstract

backgroundAcute 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.

methodsAlkynyl aminoisoquinoline and naphthyridine compounds were synthesized via Sonogashira coupling. The compounds were evaluated for their in vitro and in vivo effects on leukemia growth.

findingsThe 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.

interpretationCompounds 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.

Indexed as

AnimalsAntineoplastic AgentsApoptosisCell Cycle CheckpointsCell Line, TumorCell ProliferationCell Survivalfms-Like Tyrosine Kinase 3HumansIsoquinolinesLeukemia, Myeloid, AcuteMiceMolecular StructureMutationNaphthyridinesProtein Kinase InhibitorsAntineoplastic Agentsfms-Like Tyrosine Kinase 3isoquinolineIsoquinolinesNaphthyridinesProtein Kinase Inhibitorssrc-Family KinasesAcute myeloid leukemiaAnti-leukemic effectFLT3-ITD (D835Y/F691L) inhibitionFLT3 kinase inhibitorsSrc kinase inhibitors

Identifiers

PMID30686755
PMCPMC6413339

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.