05 June 2023
Katherine Donovan, Lead scientist, Dana-Farber Cancer Institute, Harvard Medical School speaks about her mission to map the degradable proteome
In the first edition of our new opnMe series, Katherine Donovan, (Lead Scientist at Dana-Farber Cancer Institute, Harvard Medical School) introduces the Degradation Proteomics Initiative (DPI) that she has established within Eric Fischer’s lab to provide an independent assessment of publicly available molecular degraders, such as proteolysis-targeting chimeras (PROTACs). This crowdsourcing initiative relies on submissions from the scientific community and has led to the characterization of many degrader molecules.
As a platform promoting open innovation, opnMe reached out to Katherine who evaluated and provided data on the first five PROTACs available on opnMe. The results of this independent assessment were unambiguous. In each experiment, out of the proteins quantified the PROTAC’s intended target/s was/were significantly downregulated. This underscores our mission to share only very well-characterized molecules with the scientific community.
| Degrader (opnMe code) | Intended target according to opnMe profile | Specificity confirmed by Proteomics Degradation Initiative | |
ACBI1 | SMARCA2 SMARCA4 | ||
ACBI2 | SMARCA2 | ||
| BI-0319 | PTK2 | ||
| BI-3663 | PTK2 | ||
| VZ185 | BRD7 BRD9 |
About the Fischer lab Degradation Proteomics Initiative
The availability of PROTAC technology gave rise to a new class of small molecule degraders for targets that have been previously considered undruggable. However, some published or patented degraders seem to lack thorough characterization and are less selective than originally intended. This is due in part to the fact the one of the major criteria for PROTAC molecule design, binding affinity, does not always correlate with degradation efficacy.
Katherine and her co-workers have developed a label-free, mass spectrometry-based quantitative proteomics platform allowing them to test degrader molecules in higher throughput than was previously possible. The initiative’s aims are not only related to testing the quality of the protein degrader universe but also to build an open source database to guide and accelerate degrader molecule design and ultimately understand the principles of protein degradation.
References:
- Donovan K. A., Ferguson F. M., Bushman J. M., Eleuteri N. A., Bhunia D., Seong Ryu S., Tan L., Shi K., Yue H., Liu X., Dobrovolsky D., Jiang B., Wang J., Hao M., You I., Teng M., Liang Y., Hatcher J., Li Z., Manz T. D., Groendyke B., Hu W., Nam Y., Sengupta S., Cho H., Shin I., Agius M. P., Ghobrial I. M., Ma M. W., Che J., Buhrlage S. J., Sim T., Gray N. S., Fischer E. S. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development Cell. 2020, 183(6):1714-1731.e10. DOI: 10.1016/j.cell.2020.10.038, PubMed.
- Xiong Y., Donovan K. A., Eleuteri N. A., Kirmani N., Yue H., Razov A., Krupnick N. M., Nowak R. P., Fischer E. S. Chemo-proteomics exploration of HDAC degradability by small molecule degraders Cell Chem Biol. 2021, 28(10):1514-1527.e4. DOI: 10.1016/j.chembiol.2021.07.002, PubMed.
- Fischer lab Degradation Proteomics initiative