Nutlin-3a

Name: Nutlin-3a
Brand: BOC Sciences
Price: 159 USD
Availability: MadeToOrder

CAS No.: 675576-98-4

Cat No.: BP-200004

Purity: 95%

HPLC

HNMR

MS 4.5

Nutlin-3a is a small-molecule E3 ligase ligand commonly used in PROTAC research and targeted protein degradation studies. As a potent inhibitor of the MDM2-p53 interaction, Nutlin-3a enables the recruitment of MDM2 E3 ubiquitin ligase to specific protein targets, facilitating their ubiquitination and subsequent proteasomal degradation. Nutlin-3a is particularly valuable for creating MDM2-based PROTACs, offering a strategic approach for the degradation of oncogenic or disease-associated proteins through the ubiquitin-proteasome pathway. Its application spans oncology research, cell signaling studies, and the discovery of next-generation therapeutics.

Structure of 675576-98-4

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Category

Ligand for E3 Ligase

Molecular Formula

C30H30Cl2N4O4

Molecular Weight

581.5

Appearance

White to off-white solid

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

Size	Price	Stock	Quantity
10 mg	$159	In stock

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Comprehensive PROTAC Platform
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Purity

95%

Solubility

Soluble in DMSO (5 mg/mL)

Appearance

White to off-white solid

Storage

- 20 °C

IUPACName

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

Synonyms

rebemadlin; (-)-Nutlin-3; Nutlin-3a chiral

Density

1.36 g/cm3

InChI Key

BDUHCSBCVGXTJM-WUFINQPMSA-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)/t27-,28+/m0/s1

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-3a is a small-molecule antagonist of the MDM2 (Murine Double Minute 2) protein, discovered for its potent ability to reactivate the tumor suppressor p53 by disrupting the p53-MDM2 interaction. In the context of targeted protein degradation and PROTAC (Proteolysis Targeting Chimera) research, Nutlin-3a serves as an important ligand scaffold for recruiting MDM2, an E3 ubiquitin ligase, enabling the controlled degradation of disease-associated proteins.

Mechanism

Nutlin-3a binds selectively to the p53-binding pocket of the MDM2 E3 ubiquitin ligase, blocking the interaction between MDM2 and p53. This blockade prevents p53 ubiquitination and proteasomal degradation, leading to its stabilization and activation. When used as an E3 ligase ligand in PROTAC design, Nutlin-3a is conjugated to a ligand targeting a protein of interest via a chemical linker. The resulting bifunctional molecule facilitates the formation of a ternary complex between MDM2, the PROTAC, and the target protein. This spatial proximity drives target ubiquitination and triggers its proteasomal degradation.

Applications

Nutlin-3a is a valuable building block for developing MDM2-based PROTACs aimed at targeted protein degradation for cancer research and drug discovery. Its ability to manipulate the p53-MDM2 interaction is instrumental in:

• Synthesizing MDM2-recruiting PROTACs for selective target degradation
• Investigating mechanisms of p53 pathway reactivation and p53-dependent cytotoxicity
• Designing chemical biology tools for target validation and pathway elucidation
• Advancing medicinal chemistry projects focused on E3 ligase ligand optimization
• Supporting innovative therapies for p53 wild-type tumors and related conditions

• 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 inhibitor for targeting the p53 pathway in PROTAC research.
• Facilitates efficient recruitment of MDM2 E3 ligase, expanding the toolbox for targeted protein degradation strategies.

1.MDM2 is implicated in high-glucose-induced podocyte mitotic catastrophe via Notch1 signalling.

Tang H;Lei CT;Ye C;Gao P;Wan C;Chen S;He FF;Wang YM;Su H;Zhang C J Cell Mol Med. 2017 Dec;21(12):3435-3444. doi: 10.1111/jcmm.13253. Epub 2017 Jun 23.

Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in 'post-mitosis' state and unable to regenerate. Re-entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi-nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up-regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p-H3. Genetic deletion of MDM2 partly reversed HG-induced mitotic phase re-entering of podocytes. Moreover, HG-induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin-3a, an inhibitor of MDM2-p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively.

2.Targeted nutlin-3a loaded nanoparticles inhibiting p53-MDM2 interaction: novel strategy for breast cancer therapy.

Das M;Dilnawaz F;Sahoo SK Nanomedicine (Lond). 2011 Apr;6(3):489-507. doi: 10.2217/nnm.10.102.

AIM: ;The objective of the present study is to prepare and characterize nutlin-3a loaded polymeric poly(lactide-co-glycolide) nanoparticles (NPs) surface functionalized with transferrin ligand, to deliver the encapsulated drug in a targeted manner to its site of action and to evaluate the efficacy of the nanoformulation in terms of its cellular uptake, cell cytotoxicity, cell cycle arrest, apoptosis and activation of p53 pathway at molecular level in MCF-7 breast cancer cell line.;METHOD: ;Nutlin-3a loaded poly(lactide-co-glycolide) NPs were prepared following the single oil-in-water emulsion method. Physicochemical characterization of the formulation included size and surface charge measurement, transmission electron microscopy characterization, study of surface morphology using scanning electron microscopy, Fourier-transform infrared spectral analysis and in vitro release kinetics studies. Furthermore, targeting ability of the conjugated system was assessed by cellular uptake and cell cytotoxicity studies in an in vitro cell model. Molecular basis of nutlin-3a-mediated p53 activation pathway was investigated by western blot analysis. Inhibition of cell cycle progression and apoptosis was evaluated by flow cytometry.

3.p53 directly activates cystatin D/CST5 to mediate mesenchymal-epithelial transition: a possible link to tumor suppression by vitamin D3.

Hünten S;Hermeking H Oncotarget. 2015 Jun 30;6(18):15842-56.

Cystatin D (CST5) encodes an inhibitor of cysteine proteases of the cathepsin family and is directly induced by the vitamin D receptor (VDR). Interestingly, vitamin D3 exerts tumor suppressive effects in a variety of tumor types. In colorectal cancer (CRC) cells CST5 was shown to mediate mesenchymal-epithelial transition (MET). Interestingly, vitamin D3 was shown to exert tumor suppressive effects in a variety of tumor types, including colorectal cancer (CRC). We recently performed an integrated genomic and proteomic screen to identify targets of the p53 tumor suppressor in CRC cells. Thereby, we identified CST5 as a putative p53 target gene. Here, we validated and characterized CST5 as a direct p53 target gene. After activation of a conditional p53 allele, CST5 was upregulated on mRNA and protein levels. Treatment with nutlin-3a or etoposide induced CST5 in a p53-dependent manner. These regulations were direct, since ectopic and endogenous p53 occupied a conserved binding site in the CST5 promoter region. In addition, treatment with calcitriol, the active vitamin D3 metabolite, and simultaneous activation of p53 resulted in enhanced CST5 induction and increased repression of SNAIL, an epithelial-mesenchymal transition (EMT) inducing transcription factor.

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
50 mM	0.0344 mL	0.1720 mL	0.3439 mL

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