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Identification of substituted 5-membered heterocyclic compounds as potential anti-leukemic agents.

Abstract：

:Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Ling T,Maier J,Das S,Budhraja A,Bassett R,Potts MB,Shelat A,Rankovic Z,Opferman JT,Rivas F

doi

10.1016/j.ejmech.2018.12.059

subject

Has Abstract

pub_date

2019-02-15 00:00:00

pages

391-398

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)31105-X

journal_volume

164

pub_type

杂志文章

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