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Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors

Anna Pellattiero1,2, Charlotte Quirin1,2, Federico Magrin1,2,3

  • 1Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.

Science Advances
|July 4, 2025
PubMed

Insights

Researchers identified MYLS22, a novel inhibitor targeting Optic Atrophy 1 (OPA1) GTPase activity. This discovery offers a new therapeutic strategy to enhance cancer cell apoptosis and improve treatment sensitivity.

Area of Science:

  • Mitochondrial biology
  • Cancer therapeutics
  • Biochemistry

Background:

  • Optic Atrophy 1 (OPA1) is a mitochondrial GTPase crucial for cristae remodeling, cytochrome c release, and apoptosis.
  • Elevated OPA1 levels in cancers are linked to decreased therapy response and poorer patient outcomes.
  • Targeting OPA1 GTPase activity presents a potential strategy to overcome cancer therapy resistance.

Purpose of the Study:

  • To identify and characterize novel inhibitors of OPA1 GTPase activity.
  • To evaluate the therapeutic potential of OPA1 inhibition in sensitizing cancer cells to existing therapies.
  • To validate OPA1 as a druggable target for cancer treatment.

Main Methods:

  • High-throughput screening of approximately 10,000 compounds to identify OPA1 inhibitors.
  • In vitro and cellular assays to assess the inhibitory activity and mechanism of MYLS22.
  • Structure-activity relationship studies to optimize OPA1 inhibitor efficacy, leading to Opitor-0.
  • Assessment of MYLS22 and Opitor-0 effects on mitochondrial morphology, apoptosis, and therapy sensitivity in cancer cells.

Main Results:

  • MYLS22, an N-pyrazole derivative, was identified as a reversible, noncompetitive OPA1 GTPase inhibitor.
  • MYLS22 demonstrated engagement with OPA1, inducing cristae remodeling and mitochondrial fragmentation.
  • MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy.
  • Opitor-0, derived from MYLS22, showed improved OPA1 inhibition, cytochrome c release, and therapy sensitization.
  • Neither compound exhibited toxicity in non-cancerous cells.

Conclusions:

  • OPA1 GTPase activity is a validated therapeutic target for increasing cancer cell apoptosis.
  • MYLS22 and its derivative Opitor-0 represent promising chemical probes for OPA1-targeted cancer therapy.
  • Inhibiting OPA1 can restore sensitivity to therapies like anti-Bcl-2 treatment, offering a novel approach to cancer management.

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