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

  • J Med Chem. 2026 May 28;69(10):12048-12068. doi: 10.1021/acs.jmedchem.5c03692.
Li Zheng  1 ,  Eugene Park  1 ,  Jason Lenihan  1 ,  William S R Forrest  1 ,  Xin Zhou  1 ,  Charmaine Fong  1 ,  Yangzhong Tang  1 ,  Marcus P Kelly  1 ,  Amine Driouchi  1 ,  Ali Tabatabaei  1 ,  Helen Wong  1 ,  Jesse D Vargas  1 ,  Samuel T Albright  1 ,  Zachary Howard  1 ,  Maité B Silva  1 ,  Liam A Elliott  1 ,  Michael Farley  1 ,  José Ortega  1 ,  Stephen Jones  1 ,  Xiao Chang  1 ,  Taylor Heuer  1 ,  Quan Zheng  1 ,  Huntly M Morrison  1 ,  Daniel Bracho  1 ,  Qian Du  1 ,  Jennifer Le  1 ,  Abhijit Tarafder  1 ,  Grzegorz Nawrocki  1 ,  Patric Schyman  1 ,  Lakshmi Akella  1 ,  Mai K Nguyen  1 ,  Daisy Ding  1 ,  Arnold Tao  1 ,  Fernando Rodríguez Pérez  1 ,  Kayla VanBuren  1 ,  Rohit Malik  1 ,  Melissa Dumble  1 ,  Daniel J Anderson  1 ,  Leah Cleary  1 ,  David W Piotrowski  1 ,  Hilary P Beck  1
Affiliations
  • 1. Eikon Therapeutics Inc., 230 Harriet Tubman Way, Millbrae 94030, California, United States.
PMID: 42017951 DOI: 10.1021/acs.jmedchem.5c03692
Abstract

RuvB-like 1 (RUVBL1) and RuvB-like 2 (RUVBL2) are AAA ATPases that form hetero-oligomeric complexes involved in diverse cellular functions. Increasing evidence implicates the RUVBL1/2 complex as an essential cofactor of MYC, with RUVBL1/2 inhibition reducing c-Myc levels in vitro. Herein, we report a potent RUVBL1/2 inhibitor discovered through a Single-Molecule Tracking (SMT)-driven SAR campaign. Compared with a biochemical ADP-Glo assay, which exhibited limited dynamic range and poor reproducibility under our experimental conditions, the live-cell high-throughput RUVBL SMT assay provided robust and reproducible potency measurements and correlated strongly with cell viability and MYC degradation. Multiparameter optimization yielded compound 18, which demonstrated improved efficacy in a MYC-dependent Burkitt lymphoma xenograft model at a significantly lower dose than the RUVBL1/2 inhibitor CB-6644. This work establishes SMT as a powerful tool to facilitate the drug discovery SAR campaigns and evaluates the therapeutic potential of RUVBL1/2 inhibition in MYC-dependent cancers.

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