Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases

Xin Luo; Ivonne Archibeque; Ken Dellamaggiore; Kate Smither; Oliver Homann; James Russell Lipford; Dane Mohl

doi:10.1016/j.isci.2022.103985

Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases

iScience. 2022 Feb 26;25(3):103985. doi: 10.1016/j.isci.2022.103985. eCollection 2022 Mar 18.

Authors

Xin Luo¹, Ivonne Archibeque², Ken Dellamaggiore², Kate Smither², Oliver Homann¹, James Russell Lipford², Dane Mohl²

Affiliations

¹ AMGEN Research, Amgen Inc, South San Francisco, CA 94080, USA.
² AMGEN Research, Amgen Inc, Thousand Oaks, CA 91320, USA.

Abstract

The success of small molecule therapeutics that promotes degradation of critical cancer targets has fueled an intense effort to mimic this activity with bispecific molecules called PROTACs (proteolysis targeting chimeras). The simultaneous binding of PROTACs to a ligase and target can induce proximity-driven ubiquitination and degradation. VHL and CRBN are the two best characterized PROTAC ligases, but the rules governing their cellular activities remain unclear. To establish these requirements and extend them to new ligases, we screened a panel of 56 cell lines with two potent PROTACs that utilized VHL, MZ1, or CRBN, dBET1 to induce degradation of BRD4. With notable exceptions, MZ1 was broadly active in the panel whereas dBET1 was frequently inactive. A search for predictive biomarkers of PROTAC activity found that expression and mutation of VHL and CRBN were themselves predictors of PROTAC activity in the cell line panel.

Keywords: Bioengineering; Cancer; Molecular biology.