Diarylureas as Antitumor Agents
Round 1
Reviewer 1 Report
In the paper entitled `Diarylureas as Antitumor Agents: A Review`, Catalano et. al were focused on diarylureas drugs of great importance in medicinal chemistry. In this review, they examined progress over the past 10 years in the development of new diarylureas, ureas substituted with two aromatic moieties also known as bis-aryl ureas. Diarylureas are found in numerous heterocyclic compounds with various biological activities, such as antithrombotic, antimalarial, antibacterial, antinflammatory, and anticancer. In particular, they are prominent pharmacophore in anticancer drugs. A few examples of these compound were described such as Sorafenib, Regorafenib, Linifanib, Tivozanib. They also mentioned about the combination therapy (combination studies of Sorafenib and Tivozanib with other drugs have been described), which can be very helpful when patients do not respond to therapy with only one drug.
In my opinion this review is written very well, Authors were focusing on the newest research and literature reports concerning discussed issue. Nevertheless, I have very minor and general suggestion. In my opinion the summary of these review is too general. The Authors should write some personal vision about the newest research of diarylurea, mayby confront the results from clinical phases, if they are promising or not.
Author Response
In my opinion the summary of these review is too general. The Authors should write some personal vision about the newest research of diarylurea, may by confront the results from clinical phases, if they are promising or not.
We agree with the referee and thanks for the suggestion. Some sentences were added in summary.
Author Response File: 
Author Response.docx
Reviewer 2 Report
The manuscript by Catalano et al. provides an overview of the recent development and clinical application of a series of diarylurea derivatives as anticancer agents. The manuscript is well written and structured. The work is very well updated and covers a pertinent number of scientific contribution of the last two years. Thus, the contents can be considered sufficiently innovative if compared to the last review article in this specific field (Garuti et al. Diaryl Urea: A Privileged Structure in Anticancer Agents. Current Medicinal Chemistry, 2016, 23, 1528-1548. Ref n°5 in the ms). We have just minor suggestions before publication.
_The introduction paragraph is very similar (also the figures) to that in the review article by Garuti et al. 2016. We suggest rearranging this section with some original information for example on the SAR studies on the diarylurea scaffold of compounds reported in figure 3. I think the reader would be interested in receiving some information regarding the structural determinants that seems to ensure the inhibitory potency. Considering the available crystallographic studies, a representative binding mode with relevant ligand-target interactions could also be described.
_Page 3, lines 82-85: Please correct the sentence because Atezolizumab is an immune checkpoint inhibitors (anti-PD-L1) while Bevacizumab is an anti-VEGF mab.
_Page 3, line 87: albumin-bilirubin “grade”.
_When available, provide the trade name of the examined molecules (Tivozanib, FOTIVDA; Ripretinib, QINLOCK)
Author Response
-The introduction paragraph is very similar (also the figures) to that in the review article by Garuti et al. 2016. We suggest rearranging this section with some original information for example on the SAR studies on the diarylurea scaffold of compounds reported in figure 3. I think the reader would be interested in receiving some information regarding the structural determinants that seems to ensure the inhibitory potency. Considering the available crystallographic studies, a representative binding mode with relevant ligand-target interactions could also be described.
We agree with the reviewer and thanks for this suggestion. We have added a paragraph “2.6. Mechanisms of inhibition of diarylureas” after the description of diarylureas in therapy, and not in the introduction because we refer to chemical structures of the drugs depicted in Figure 3. In this paragraph recent mechanisms proposed for inhibition are described. However, we thought not to rewrite introduction as in our opinion it may be useful to better understand diarylureas mechanisms.
-Page 3, lines 82-85: Please correct the sentence because Atezolizumab is an immune checkpoint inhibitors (anti-PD-L1) while Bevacizumab is an anti-VEGF mab.
Thank you for this suggestion. The sentence has been changed. CTLA-4 has been deleted also in abbreviations
-Page 3, line 87: albumin-bilirubin “grade”.
Thank you for this suggestion. “grade” has been added
-When available, provide the trade name of the examined molecules (Tivozanib, FOTIVDA; Ripretinib, QINLOCK).
Thank you for this suggestion. FOTIVDA® and QINLOCKTM have been added.
Author Response File: Author Response.docx
