Attaining New Heights in Protein Degradation Therapy Research
Monte Rosa Therapeutics
Small molecule-induced protein degradation is a promising modality in novel, highly targeted cancer therapy development and beyond. Within this realm, Monte Rosa Therapeutics in Boston, Massachusetts, has particular expertise working with small molecule degraders known as molecular glues. Within a diseased or otherwise undesirable cell, these molecular glues bind a targeted protein to a ligase complex so that the targeted protein is redirected for destruction by the cell’s naturally occurring ubiquitin-proteasome system. This novel method invites therapeutic potential in previously undruggable molecular spaces.
Nooreen Rubin works in the company’s biology group and is also involved with the screening group. As new protein targets are identified, she says that they have used Promega’s luminescence-based Nano-Glo HiBiT Lytic Detection System to evaluate endogenous levels of proteins in potential targets. “This assay provides endpoint data, which has value, but it’s just a single snapshot in time,” Nooreen says. “We wanted to dig deeper; identify what was happening over time, and pinpoint exactly when effects occur.” This meant migrating to kinetic analyses using a microplate reader capable of continuous detection over 24 hours. Proper cell conditions over the assay duration requires precise environmental control, but the group didn’t want to sacrifice valuable incubator space.
Nooreen recalls that years ago at a different company, she participated in a demonstration of BioTek’s BioSpa 8 Automated Incubator, which includes temperature and CO2/O2 control for up to eight microplates and can be linked to a microplate reader for start-to-finish workflow automation. She contacted the local BioTek representative, who arranged for an evaluation of the BioSpa along with the Synergy Neo2 Hybrid Multi-Mode Reader; she also procured Promega’s Nano-Glo Endurazine Live Cell Substrate to use in conjunction with the HiBiT system to facilitate the extended assay duration.
The BioSpa/Neo2 evaluation yielded results that were immediately impactful, and the team quickly decided to purchase a BioSpa/Neo2 system of their own. Now that it’s installed, Nooreen finds herself using the system every week and sometimes every day. “It amazes me just how easy it is to set up and use, and we always get awesome data from it – the curves are truly incredible,” she says. For instance, in a single 384-well plate experiment, she can see that one compound degrades protein within 30 minutes while a different compound takes four hours, and it’s simple to run dose response experiments on promising compounds. The system will also help her to seamlessly transition the workflow into a 1536-well microplate format, in response to their growing compound library. Nooreen’s Boston colleagues, as well as those in Monte Rosa’s Basel, Switzerland location, are excited because they now have a different and much more granular perspective of the protein degradation studies that enable them to quickly make well-informed decisions.
Monte Rosa’s protein degradation research is also supported by BioTek’s Cytation 5 Cell Imaging Multi-Mode Reader with a dedicated BioSpa for image proliferation and fluorescent signaling studies as well as the MultiFlo FX Multi-Mode Dispenser.
Nooreen summarizes her experience noting, “At Monte Rosa, our goal is to make a significant difference in the healthcare market, and I’m both excited and hopeful about what we can achieve with our BioTek products.”
A 10-point dose response kinetics of protein degradation. HiBiT/LgBiT cells were pre-treated with Endurazine (Promega) and then treated with compound. Fluorescent signal was measured every 43 minutes on the Synergy Neo2 Hybrid Multi-Mode Reader.
For Research Use Only. Not for use in diagnostic procedures.
To learn more about Monte Rosa Therapeutics , visit their web site.
Thanks to Nooreen Rubin for sharing her BioTek experience.