Related Experiment Video

Updated: Oct 8, 2025

Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor
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Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor

Published on: October 26, 2017

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Discovery and Lead Optimization of Benzene-1,4-disulfonamides as Oxidative Phosphorylation Inhibitors

Ding Xue1, Yibin Xu1, Armita Kyani1

  • 1Departments of Medicinal Chemistry, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.

Journal of Medicinal Chemistry
|January 4, 2022
PubMed

Insights

Researchers developed novel inhibitors targeting oxidative phosphorylation (OXPHOS) to treat cancers relying on aerobic metabolism. A lead compound demonstrated potent OXPHOS inhibition and significant efficacy in a pancreatic cancer model.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Oxidative phosphorylation (OXPHOS) is crucial for aerobic metabolism in certain cancers.
  • Targeting OXPHOS presents a promising therapeutic strategy for these malignancies.

Purpose of the Study:

  • To discover and optimize novel inhibitors of oxidative phosphorylation.
  • To investigate the structure-activity relationship (SAR) of these inhibitors.
  • To evaluate the therapeutic potential of lead compounds in preclinical cancer models.

Main Methods:

  • Phenotypic screening using a galactose-containing medium to identify cytotoxic compounds.
  • Multi-parameter optimization of hit compounds.
  • Biochemical assays to assess inhibition of complex I and adenosine triphosphate (ATP) production.
  • In vivo efficacy studies in a syngeneic pancreatic cancer model.

Main Results:

  • Identified benzene-1,4-disulfonamide as a hit compound.
  • Optimized to discover compound 65 (DX3-235) with nanomolar inhibition of OXPHOS and significant cytotoxicity.
  • Compound 64 (DX3-234), an analogue of 65, demonstrated good tolerability in mice and efficacy as a single agent in a pancreatic cancer model.

Conclusions:

  • Novel, potent, and selective OXPHOS inhibitors were discovered and optimized.
  • Compound 64 shows promise for pancreatic cancer treatment, warranting further investigation.
  • Targeting OXPHOS is a viable therapeutic strategy for cancers dependent on aerobic metabolism.

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