Nutlin-3

Name: Nutlin-3
Brand: BOC Sciences
Price: 519 USD
Availability: MadeToOrder

CAS No.: 548472-68-0

Cat No.: BP-200068

Purity: >98% 4.5

Nutlin-3 is a potent and selective MDM2 antagonist widely utilized as an E3 ligase ligand in PROTAC drug discovery. It specifically blocks the interaction between MDM2 and the tumor suppressor p53, leading to the stabilization and activation of p53. In PROTAC research, Nutlin-3’s scaffolding allows for efficient recruitment of the MDM2 E3 ubiquitin ligase to target proteins, enabling their ubiquitination and subsequent proteasomal degradation. As a small molecule developed for targeted protein degradation, Nutlin-3 is an essential tool in oncology research, allowing scientists to design and optimize MDM2-based PROTACs for the treatment of cancer and other diseases linked to dysregulated p53 pathways.

Structure of 548472-68-0

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Category

Ligand for E3 Ligase

Molecular Formula

C30H30Cl2N4O4

Molecular Weight

581.49

Related CAS

890090-75-2

Appearance

White Solid

* For research and manufacturing use only. Not for human or clinical use.

Size	Price	Stock	Quantity
100 mg	$519	In stock

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Capabilities & Facilities

Comprehensive PROTAC Platform
Scientific Expertise & Technical Support
Custom Synthesis & Design Service
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Popular Publications Citing BOC Sciences Products

Purity

>98%

Solubility

Soluble in DMSO.

Appearance

White Solid

ShelfLife

2 years

Storage

Store at -20°C

IUPACName

4-[4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one

Synonyms

(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 4-[4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one

InChI Key

BDUHCSBCVGXTJM-UHFFFAOYSA-N

InChI

InChI=1S/C30H30Cl2N4O4/c1-18(2)40-25-16-23(39-3)12-13-24(25)29-34-27(19-4-8-21(31)9-5-19)28(20-6-10-22(32)11-7-20)36(29)30(38)35-15-14-33-26(37)17-35/h4-13,16,18,27-28H,14-15,17H2,1-3H3,(H,33,37)

SMILES

CC(C)OC1=C(C=CC(=C1)OC)C2=NC(C(N2C(=O)N3CCNC(=O)C3)C4=CC=C(C=C4)Cl)C5=CC=C(C=C5)Cl

Background Introduction

Nutlin-3 is a small-molecule inhibitor originally developed as an antagonist of the MDM2-p53 interaction. It belongs to the class of cis-imidazoline analogs and is widely recognized for its ability to stabilize and activate the tumor suppressor protein p53 by preventing its ubiquitination and degradation. While Nutlin-3 was first explored as an anti-cancer agent through direct modulation of p53 signaling, more recently, it has gained traction as a high-affinity ligand for the MDM2 E3 ubiquitin ligase in the context of PROTAC (Proteolysis Targeting Chimera) technology.

Mechanism

Nutlin-3 functions by selectively binding to the MDM2 E3 ubiquitin ligase, blocking its interaction with p53, thereby inhibiting the ubiquitination and subsequent degradation of p53. In the PROTAC framework, Nutlin-3 is employed as the E3 ligase-recruiting element, allowing engineered bifunctional molecules to harness MDM2-mediated ubiquitination in a target-specific manner. When conjugated via a suitable linker to a ligand for a protein of interest, the resulting PROTAC brings the target protein in proximity to the MDM2 E3 ligase, facilitating targeted ubiquitination and proteasomal degradation of the disease-associated protein.

Applications

Nutlin-3 is a valuable tool compound for both fundamental cancer biology and advanced targeted protein degradation research. Its primary applications include:

• Serving as an MDM2 ligand moiety in the construction of MDM2-based PROTACs for targeted protein degradation strategies.
• Facilitating studies of the p53-MDM2 regulatory axis in cancer and cellular stress responses.
• Supporting the development of novel therapeutics by enabling the degradation of proteins previously considered 'undruggable' via MDM2 recruitment.
• Providing a scaffold for medicinal chemistry optimization, structure-activity relationship (SAR) exploration, and custom degrader design in both academic and industrial drug discovery programs.

• High-purity compound verified by HPLC, NMR, and LC-MS
• Consistent batch-to-batch reproducibility with complete QC documentation
• Supplied with COA, MSDS, and analytical data for traceability
• Reliable global shipping with stability-guaranteed packaging
• Dedicated technical support and optional custom synthesis service
• Demonstrates strong binding affinity to CRBN, VHL, or other E3 ligases
• Enables stable E3 ligase recruitment for targeted protein degradation
• Potent and selective MDM2 antagonist, enabling efficient recruitment of E3 ligase for target protein degradation.
• Widely validated scaffold for designing MDM2-based PROTACs, supporting rapid development of next-generation therapeutics.

1.Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas.

Daniele S, La Pietra V, Barresi E, Di Maro S, Da Pozzo E, Robello M, La Motta C, Cosconati S, Taliani S, Marinelli L, Novellino E, Martini C, Da Settimo F. J Med Chem. 2016 Apr 6. [Epub ahead of print]

In Glioblastoma Multiforme (GBM), Translocator Protein (TSPO) and Murine Double Minute (MDM2)/p53 represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a Structure-Activity-Relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics, and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of Temozolomide; (v) directed its effects preferentially toward tumour cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent which is worthy to be further developed for a therapeutic approach against GBM, where the downstream p53 signalling is intact and TSPO is over-expressed.

2.Integrative modeling of multi-omics data to identify cancer drivers and infer patient-specific gene activity.

Pavel AB1,2, Sonkin D3, Reddy A4. BMC Syst Biol. 2016 Feb 11;10(1):16. doi: 10.1186/s12918-016-0260-9.

BACKGROUND: High throughput technologies have been used to profile genes in multiple different dimensions, such as genetic variation, copy number, gene and protein expression, epigenetics, metabolomics. Computational analyses often treat these different data types as independent, leading to an explosion in the number of features making studies under-powered and more importantly do not provide a comprehensive view of the gene's state. We sought to infer gene activity by integrating different dimensions using biological knowledge of oncogenes and tumor suppressors.

3.Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner.

Esfandiari A1, Hawthorne TA1, Nakjang S2, Lunec J3. Mol Cancer Ther. 2016 Mar;15(3):379-91. doi: 10.1158/1535-7163.MCT-15-0651. Epub 2016 Feb 1.

Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53(Ser15) phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non-growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.

4.Monitoring Ligand-Induced Protein Ordering in Drug Discovery.

Grace CR1, Ban D1, Min J2, Mayasundari A2, Min L1, Finch KE3, Griffiths L4, Bharatham N1, Bashford D1, Kiplin Guy R2, Dyer MA5, Kriwacki RW6. J Mol Biol. 2016 Mar 27;428(6):1290-303. doi: 10.1016/j.jmb.2016.01.016. Epub 2016 Jan 23.

While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	1.7197 mL	8.5986 mL	17.1972 mL
5 mM	0.3439 mL	1.7197 mL	3.4394 mL
10 mM	0.1720 mL	0.8599 mL	1.7197 mL

How does Nutlin-3 exert its anti-tumor effects?

Nutlin-3 plays an anti-tumor role by binding with MDM2, inhibiting the interaction between MDM2 and p53, and activating p53 to induce cell apoptosis.

29/10/2019

What is the IC50 value of Nutlin-3 inhibiting MDM2-p53?

The IC50 value of Nutlin-3 inhibiting MDM2-p53 was 90 nM.

25/1/2020

What is the activity of Nutlin-3 in vivo?

Nutlin-3 can suppress the growth of xenograft tumors derived from human osteosarcoma or leukemia cells, the anti-tumor activity of Nutlin-3 even at the dose of 200 mg/kg per oral administration is marginal in an HCT116-derived xenograft tumor model.

25/8/2021

inhibit MDM2 binding to p53

We bought Nutlin-3 to inhibit MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling.

25/6/2020

activate p53

Working well in the lab. Co-treatment of p53-positive HCT116 cells with 1 μM of Inauhzin and 2 μM of Nutlin-3 more significantly activated p53 as measured by its protein level as well as the level of its target p21, PUMA or cleaved PARP as indication of apoptosis.

27/10/2022

induce p53 and p21WAF expression

Worked adequately. Nutlin-3 induces p53 and p21WAF expression in a dose-dependent manner in 22RV1 cells.

09/11/2018

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂