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Updated: Apr 23, 2026

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Rapid Optimization Enabled by Single-Molecule Tracking: Discovery of a Potent RUVBL1/2 Inhibitor to Evaluate the

Li Zheng1, Eugene Park1, Jason Lenihan1

  • 1Eikon Therapeutics Inc., 230 Harriet Tubman Way, Millbrae 94030, California, United States.

Journal of Medicinal Chemistry
|April 22, 2026
PubMed

Insights

Researchers developed a novel RUVBL1/2 inhibitor using Single-Molecule Tracking (SMT) assays for drug discovery. This inhibitor effectively reduced MYC levels and showed therapeutic potential in MYC-dependent cancers.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • RuvB-like 1 (RUVBL1) and RuvB-like 2 (RUVBL2) are AAA ATPases forming complexes crucial for cellular functions.
  • The RUVBL1/2 complex acts as a MYC cofactor, and its inhibition reduces c-MYC levels.

Purpose of the Study:

  • To discover potent RUVBL1/2 inhibitors for MYC-dependent cancers.
  • To establish Single-Molecule Tracking (SMT) as a viable method for drug discovery SAR campaigns.

Main Methods:

  • Utilized a Single-Molecule Tracking (SMT) assay for high-throughput screening and structure-activity relationship (SAR) studies.
  • Compared SMT assay performance with a biochemical ADP-Glo assay.
  • Conducted multiparameter optimization to develop potent inhibitors.
  • Evaluated compound efficacy in a MYC-dependent Burkitt lymphoma xenograft model.

Main Results:

  • The live-cell SMT assay provided robust and reproducible potency measurements, outperforming the ADP-Glo assay.
  • SMT assay results strongly correlated with cell viability and MYC degradation.
  • Optimized compound 18 demonstrated superior efficacy in a xenograft model compared to existing inhibitors.
  • Compound 18 achieved efficacy at a significantly lower dose than CB-6644.

Conclusions:

  • Single-Molecule Tracking (SMT) is a powerful tool for drug discovery SAR campaigns.
  • RUVBL1/2 inhibition presents a promising therapeutic strategy for MYC-dependent cancers.
  • The developed inhibitor shows significant potential for treating these cancers.

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