1. Academic Validation
  2. Identification of substituted 5-membered heterocyclic compounds as potential anti-leukemic agents

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

  • Eur J Med Chem. 2019 Feb 15:164:391-398. doi: 10.1016/j.ejmech.2018.12.059.
Taotao Ling 1 Julie Maier 1 Sourav Das 1 Amit Budhraja 2 Rachel Bassett 1 Malia B Potts 2 Anang Shelat 1 Zoran Rankovic 1 Joseph T Opferman 3 Fatima Rivas 4
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105-3678, USA.
  • 2 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105-3678, USA.
  • 3 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105-3678, USA. Electronic address: joseph.opferman@stjude.org.
  • 4 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105-3678, USA. Electronic address: fatima.rivas@stjude.org.
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.

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