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MDM2 inhibitor (-)-Nutlin 3a Small Molecule (Tool Compound)

Invented by Prof Bernard Golding at University of Newcastle upon Tyne

Info

Antigen/Gene or Protein Targets MDM2/p53
Synonyms (-)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-2-one
CAS No.: 675576-98-4
Type Inhibitor
Relevance MDM2 inhibitor (-)-Nutlin 3a is a wild-type p53 activator which acts by binding and inhibiting MDM2. Loss of p53 activity, by deletion, mutation, or MDM2 overexpression, is the most common event in the development and progression of cancer, while the restoration of endogenous p53 function results in tumor regression in vivo. In this context, the rescue of the impaired p53 activity and resensitization to apoptosis in cancer cells by disrupting the MDM2−p53 interaction offers an opportunity for anticancer therapeutics.
On Target IC50 90 nM
Selectivity Much lower effect on MDMX. Most effective on tumors with wild type p53.
Molecular Formula C30H30Cl2N4O4
Molecular Weight (g/mol) 581.49
In vivo applications Nutlin-3a suppresses xenograft growth in a dose-dependent fashion with the highest dose (200 mg/kg) showing a substantial tumor shrinkage. Nutlin-3 is a selective activator of the p53 pathway in vivo and highly efficacious against SJSA-1 osteosarcoma tumors. Tumors with wild-type p53 and mdm2 gene amplification will respond best to therapy with Nutlin-3a.
In vitro applications Nutlin-3a displaces p53 from the binding pocket of MDM2 and thereby releases p53 from inhibition and proteasomal degradation, leading to induction of its downstream targets, cell cycle arrest, and apoptosis. Seven days of incubation with 10 μM nutlin-3a led to >90% inhibition of NIH3T3 cells’ growth. Nutlin-3a stabilizes and activates p53, and induces p21 expression in a dose-dependent manner. Nutlin-3a effectively depletes the S-phase compartment to 0.2-2% and increases the G1- and G2/M-phase compartments. Nutlin-3a induces apoptosis in ~60% of SJSA-1 and MHM cells after 40 h, which increased further after 60 h (85% and 65%, respectively)
Research Area Cancer, Cell Cycle, Epigenetics & Nuclear Signalling

References: 2 entries

Bertamino et al. 2013. J Med Chem. 56(13):5407-21. PMID: 23802716.

Vassilev et al. 2004. Science. 303(5659):844-8. PMID: 14704432.


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References: 2 entries

Bertamino et al. 2013. J Med Chem. 56(13):5407-21. PMID: 23802716.

Vassilev et al. 2004. Science. 303(5659):844-8. PMID: 14704432.


Add a reference

References: 2 entries

Bertamino et al. 2013. J Med Chem. 56(13):5407-21. PMID: 23802716.

Vassilev et al. 2004. Science. 303(5659):844-8. PMID: 14704432.


Add a reference


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