Rapid Optimization Enabled by Single-Molecule Tracking: Discovery of a Potent RUVBL1/2 Inhibitor to Evaluate the Targeting of MYC-Driven Cancers
Year: 2026
Type: article
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.
Source: Journal of Medicinal Chemistry
Authors: Li Zheng, Eugene Park, Jason Lenihan, William S. R. Forrest, Xin Zhou, Charmaine Fong, Yangzhong Tang, Marcus P. Kelly, Amine Driouchi, Ali Tabatabaei, Helen Wong, Jesse D. Vargas, Samuel T. Albright, Zachary Howard, Maité B. Silva, Liam A. Elliott, Michael Farley, José Ortega, Stephen Jones, Xiao Chang, Taylor Heuer, Quan Zheng, Huntly M. Morrison, Daniel Bracho, Qian Du, Jennifer Le, Abhijit Tarafder, Grzegorz Nawrocki, Patric Schyman, Lakshmi Akella, Mai K. Nguyen, Daisy Ding, Arnold Tao, Fernando Rodríguez Pérez, Kayla VanBuren, Rohit Malik, Melissa Dumble, Daniel J. Anderson, Leah Cleary, David W. Piotrowski, Hilary P. Beck
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W7155162855