Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 μM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 μM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.
Pharmacology, Toxicology and Pharmaceutical Science
4
4%
Medicine and Dentistry
4
4%
Other
4
4%
Unknown
23
24%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 31. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 31 March 2026.
All research outputs
#1,493,189
of 30,703,623 outputs
Outputs from Journal of Medicinal Chemistry
#373
of 25,307 outputs
Outputs of similar age
#6,994
of 227,433 outputs
Outputs of similar age from Journal of Medicinal Chemistry
#2
of 136 outputs
Altmetric has tracked 30,703,623 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 95th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 25,307 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.5. This one has done particularly well, scoring higher than 98% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 227,433 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 96% of its contemporaries.
We're also able to compare this research output to 136 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 98% of its contemporaries.
