Synthesis, Structure-Activity Relationships, and Antitumor Activities of Quinoxiline-Containing Inhibitors of the

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Updated: Jan 17, 2026

A Quantitative Assay to Study Protein:DNA Interactions, Discover Transcriptional Regulators of Gene Expression, and Identify Novel Anti-tumor Agents
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A Quantitative Assay to Study Protein:DNA Interactions, Discover Transcriptional Regulators of Gene Expression, and Identify Novel Anti-tumor Agents

Published on: August 31, 2013

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Chandra Bhushan Mishra1, Xin Li1,2, Bala Krishna Moku1

  • 1Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.

Journal of Medicinal Chemistry
|September 16, 2025
PubMed

Insights

New quinoxaline compounds effectively inhibit protein-protein interactions in Mixed Lineage Leukemia (MLL)-rearranged leukemia. Compound 17 shows promise as a targeted therapy, demonstrating antitumor activity and favorable pharmacokinetics in preclinical models.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Mixed Lineage Leukemia (MLL) gene rearrangements are a significant cause of infant acute leukemia and contribute to adult cases, often with poor prognoses.
  • Targeting protein-protein interactions (PPIs) involving MLL fusion partners and DOT1L is a key strategy for MLL-rearranged (MLL-r) leukemia treatment.

Purpose of the Study:

  • To synthesize and evaluate novel quinoxaline compounds as inhibitors of MLL-r leukemia-associated PPIs.
  • To identify potent and selective inhibitors with potential therapeutic applications.

Main Methods:

  • Synthesis of 67 quinoxaline compounds.
  • In vitro testing for inhibition of MLL fusion partner PPIs and cellular proliferation.
  • Structure-activity relationship (SAR) analysis.
  • In vivo evaluation of compound 17 in a mouse model of MLL-r leukemia.

Main Results:

  • Four compounds (16, 17, 59, 63) demonstrated potent PPI inhibition (IC50: 0.35-1.5 μM).
  • Inhibitors suppressed MLL target genes (Myc, Meis1) and selectively inhibited leukemia cell proliferation (EC50: as low as 0.84 μM).
  • Compound 17 exhibited significant antitumor efficacy and favorable pharmacokinetics in a preclinical MLL-r leukemia mouse model without apparent toxicity.

Conclusions:

  • Novel quinoxaline derivatives are effective inhibitors of MLL-r leukemia-associated PPIs.
  • Compound 17 represents a promising pharmaceutical lead for MLL-r leukemia treatment due to its efficacy, selectivity, and pharmacokinetic profile.

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