PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives

Round 1

Reviewer 1 Report

This is a well-written and informative review article that focuses on PROTACs’ potential applications in ovarian cancer. It is evident that the authors have put in tremendous amount of time and effort to compile all the information around the topic, and overall, they did a very good job of writing the manuscript. I would recommend accept after minor revision.

1.       Line 58, “RING-Between RING-RING” should be “RING-between-RING”

2.       Line 94/95, “…VHL recruiting PROTACs are advantageous in cancer due to higher expression in tumor relative to normal tissue, increasing tumor selectivity.” please check accuracy of this statement. VHL is in general ubiquitously expressed and because its tumor suppressor role, it shouldn’t be over-expressed in cancer cells.

3.       Line 101-103, “…comes with the fact that mouse and human cereblon are divergent, with mouse cereblon having limited binding capability to human cereblon ligands such as thalidomide.” Please check the accuracy of this statement. The difference between human/mouse is that there is single mutation in mouse CRBN, which does not affect binding to iMiDs but make it not suitable for recruiting several neosubstrates of CRBN.

4.       Line 125-126, 16 may not be an appropriate reference, consider to cite “Burke et al., PMID: 35547806”

5.       It will be nice if the authors can include the structures of PROTACs mentioned.

Author Response

see attached

Author Response File: Author Response.docx

Reviewer 2 Report

1. What are the primary treatment modalities for epithelial ovarian cancer (EOC), and what factors determine the choice between primary debulking surgery and interval debulking surgery?

2. Despite advancements in treatment approaches such as VEGF inhibitors and PARP inhibitors, what is the primary challenge in managing ovarian cancer?

3. ow does the introduction lay the groundwork for discussing the potential role of proteolysis targeting chimeras (PROTACs) in addressing the challenges of ovarian cancer treatment?

4. Can you describe the process by which ubiquitin is conjugated to target proteins within the UPS?

5. How do E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ligases collaborate in the ubiquitination process?

6. What is the significance of polyubiquitination through the K48 residue of ubiquitin in the UPS pathway?

7. Can you explain the distinction between the U-box/RING classes and the HECT/RBR classes of E3 ligases in the ubiquitination process?

8. Can you explain the significance of each component of PROTAC molecules: the warhead, linker motif, and E3 ligase recruiting ligand?

9. What were some of the initial protein targets of PROTACs, and how were the E3 ligase recruiting moieties designed for these early PROTACs?

10.How has the discovery of additional small molecule ligands for E3 ligases, such as von Hippel-Lindau (VHL) and cereblon, expanded the range of available PROTACs?

Author Response

see attached

Author Response File: Author Response.docx