The work by Shaima Abdalla and Zary Forghany and co-workers/authors describes in good detail the seach
for ETS-DNA-binding inbibitors as potential tool to inhibit the essential role for ETS type transcription factors
in tumor development. The work describes the screen of a large fragment library using DNA-binding domain
fragments and oligonucleotide binding sites. While the assay itself is very well described, the complexity of
the library and the initial screening results are not very clear. I particular it remains elusive what type of
potential fragments are present in the library analyzed and how the intial pooling of fragments was performed.
Given the very similar structure of the potential specific inhibitors presented, it would be improtant to get a
better guidance in the manuscript to understand the very limited structural diversity obtained and used in the
more detailed in vitro and in vivo assays. I also do not understand how the 398,892 compounds in the ibrary
were validated? Looking at the more detailed analysis on interference with specific DNA-binding assays, it is
quite impressive how the structurally very similar compounds (figure 3 B, C) show this interesting spcificity for
the different ETS type transcription factor DNA binding. What I do not understand is why no resutls for
compounds E are shown. Becuase of the strong untiproliferative effecte of compound A and D in the cell
based assay. It is not surprising that the sprouting in the assay in figure 4 A, B is drustically inhibited. Thus
while this assay shows potential antoangiogenesis activity, it si not clear if this is specific are due to the
general anti-proliferative activity of the two compounds. The lack of DNA-damage and thus potential
genotoxicity, makes the compounds presented quite interesting as potential anti-angiogentic compounds. Still
it is not completely clear if the effect observed is specifically mediated through ETS DNA-binding inhibition.
Besides the points mentioned above, another minor point that should be addressed is the presentation of the
results in figure 2 C. Here the input lane is missing in the second panel.

Comments on revised version FEBSL-24-1131.R1 the manuscript has clearly improved with the revision and all my points addressed in my initial review have been adressed.

There are only two minor points
-- why is the signal in Figure 2 C so much weaker than in the fragment binding lanes?

-- although the story is quite complete I miss a better eplanation for the role of the fragment binding assay and its contribution to the identification and selection in the discussion of the manuscript, this would make the paper more clear for less spezialized readers.