Nutlin-3a chiral (Synonyms: Nutlin 3a)

Nutlin-3a chiral, an active isomer of Nutlin-3, is a murine double microbody 2 (MDM2) antagonist with IC50 value of 0.09μM . Nutlin-3a chiral inhibits MDM2-p53 interaction and activates wild-type p53, inducing cell cycle arrest and apoptosis^[2].

Incubation with 10 μm Nutlin-3a chiral for 7 days resulted in > 90% inhibition of NIH/3T3 cell growth but did not affect MEF proliferation, in which both targets of the drug were eliminated^[3].

Nutlin-3a chiral was able to increase the sensitivity to BBR and certain NAX compounds. The effects of Nutlin-3a chiral were usually more substantial in those cells containing an introduced WT TP53 gene^[6]. Nutlin-3a chiral binds MDM2 in the TP53-bindingpocket, thereby interfering with MDM2-directed TP53 degradation. This has been shown to cause cell cycle arrest, growth inhibitionand apoptosis in both solid tumors and lymphoid neoplasms.In mantle cell lymphoma(MCL), Nutlin-3a chiral can inhibit cell growth and activate apoptosis in bothwt-TP53(IC50 of 1 to 10μM) and mt-TP53(IC50 of 22.5μM) cells^[4]. Nutlin-3a chiral can also effectcell cycle in gastric cancer cell lines. It induces G1 arrest inMKN-45 and SNU-1 cell lines^[5].LA-N-5(human neuroblastoma) and SMS-KCNR cells pretreated with Nutlin-3a chiral were significantly more susceptible to DNAM-1-engineered NK cells than NK cells transfected with the empty vector suggesting that the combined use of DNAM-1-chimeric receptor-engineered NK cells and Nutlin-3a chiral may represent a novel therapeutic approach for the treatment of solid tumors, such as NB, carrying dysfunctional p53^[7].

In Sjsa-1 tumor-bearing nude mice, Nutlin-3a chiral inhibited xenograft growth in a dose-dependent manner, with the highest dose (200 mg/kg) showing significant tumor shrinkage^[3].

References:
[1]: Yang X, Liu J, et,al. miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities. Oncogenesis. 2021 Feb 12;10(2):15. doi: 10.1038/s41389-021-00304-3. PMID: 33579899; PMCID: PMC7881152.
[2]: Crane EK, Kwan SY, et,al. Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas. PLoS One. 2015 Aug 6;10(8):e0135101. doi: 10.1371/journal.pone.0135101. PMID: 26248031; PMCID: PMC4527847.
[3]: Tovar C, Rosinski J, et,al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1888-93. doi: 10.1073/pnas.0507493103. Epub 2006 Jan 27. PMID: 16443686; PMCID: PMC1413632.
[4]: Roscoe I, Parker M, et,al. Human Serum Albumin and the p53-Derived Peptide Fusion Protein Promotes Cytotoxicity Irrespective of p53 Status in Cancer Cells. Mol Pharm. 2018 Nov 5;15(11):5046-5057. doi: 10.1021/acs.molpharmaceut.8b00647. Epub 2018 Oct 10. PMID: 30226785.
[5]: Chen R, Zhou J, et,al. A Fusion Protein of the p53 Transaction Domain and the p53-Binding Domain of the Oncoprotein MdmX as an Efficient System for High-Throughput Screening of MdmX Inhibitors. Biochemistry. 2017 Jun 27;56(25):3273-3282. doi: 10.1021/acs.biochem.7b00085. Epub 2017 Jun 14. PMID: 28581721.
[6]: Abrams SL, Akula SM, et,al. Effects of the MDM2 inhibitor Nutlin-3a on sensitivity of pancreatic cancer cells to berberine and modified berberines in the presence and absence of WT-TP53. Adv Biol Regul. 2022 Jan;83:100840. doi: 10.1016/j.jbior.2021.100840. Epub 2021 Nov 23. PMID: 34866036.
[7]: Focaccetti C, Benvenuto M, et,al. DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study. Front Immunol. 2022 Jul 28;13:886319. doi: 10.3389/fimmu.2022.886319. PMID: 35967339; PMCID: PMC9367496.