Nutlin carboxylic acid

Name: Nutlin carboxylic acid
Brand: BOC Sciences
Rating: 5 (1 reviews)

CAS No.: 2249750-27-2

Cat No.: BP-200021 4.5

Nutlin carboxylic acid is a versatile small-molecule ligand optimized for PROTAC design, particularly in targeting the MDM2 E3 ligase pathway. As an MDM2 ligand, it enables the recruitment of the MDM2 ubiquitin E3 ligase complex for targeted protein degradation. Nutlin carboxylic acid features a terminal carboxyl group, facilitating efficient conjugation to various linkers in bifunctional molecules. This compound is essential for researchers developing MDM2-based PROTACs, molecular glues, or targeted protein degradation tools. Its applications span oncology, cell biology, and novel therapeutic development, supporting the exploration of p53 pathway modulation and other MDM2-related mechanisms within the expanding field of targeted protein degradation.

Structure of 2249750-27-2

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Category

Ligand for E3 Ligase

Molecular Formula

C32H32Cl2N4O6

Molecular Weight

639.53

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

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Comprehensive PROTAC Platform
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Solubility

10 mM in DMSO

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

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Room temperature in continental US; may vary elsewhere

Synonyms

Nutlin carboxylic acid; MDM2 ligand 1; E3 ligase Ligand 16

SMILES

O=C(N1C(C2=C(C=C(C=C2)OC)OC(C)C)=N[C@@H](C3=CC=C(C=C3)Cl)[C@H]1C4=CC=C(C=C4)Cl)N5CC(N(CC(O)=O)CC5)=O

Background Introduction

Nutlin derivatives are small-molecule ligands that selectively bind to mouse double minute 2 homolog (MDM2), an E3 ubiquitin ligase. Nutlin compounds were originally developed as potent antagonists of the MDM2-p53 interaction, thereby reactivating p53 tumor suppressor pathways in cancer therapy. Nutlin carboxylic acid is a functionalized Nutlin analogue possessing a carboxyl group which provides a convenient handle for linker attachment, making it valuable for targeted protein degradation research including PROTAC (Proteolysis Targeting Chimera) technology.

Mechanism

Nutlin carboxylic acid functions as an MDM2 E3 ligase ligand, enabling the recruitment of the MDM2 ubiquitin ligase complex in PROTAC design. By binding to MDM2, it facilitates the proximity-induced ubiquitination and proteasomal degradation of target proteins when linked to a specific ligand for the protein of interest. The carboxyl group serves as an effective conjugation site for chemical linkers, optimizing the synthesis and versatility of bifunctional degraders.

Applications

Nutlin carboxylic acid is employed as a key building block in the synthesis of MDM2-based PROTACs and heterobifunctional degraders. The presence of a carboxyl handle streamlines the assembly of conjugates for drug discovery, targeted protein degradation studies, and biological tool development.

Main applications include:

• Construction of PROTACs targeting oncogenic and regulatory proteins via MDM2-mediated degradation
• Chemical biology research and validation of new targets
• SAR (structure-activity relationship) exploration and optimization of E3 ligase ligands
• Custom synthesis for pharmaceutical research, lead optimization, and academic investigations focused on MDM2-utilizing degradation pathways

• 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
• High affinity MDM2 ligand enables selective targeting for PROTAC development.
• Facilitates effective degradation of p53-interacting proteins for oncology research applications.

1. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia

E McCormack, I Haaland, G Venås, R B Forthun, S Huseby, G Gausdal, S Knappskog, D R Micklem, J B Lorens, O Bruserud, B T Gjertsen Leukemia. 2012 May;26(5):910-7.doi: 10.1038/leu.2011.315.Epub 2011 Nov 8.

Although TP53 mutations are rare in acute myeloid leukemia (AML), wild type p53 function is habitually annulled through overexpression of MDM2 or through various mechanisms including epigenetic silencing by histone deacetylases (HDACs). We hypothesized that co-inhibition of MDM2 and HDACs, with nutlin-3 and valproic acid (VPA) would additively inhibit growth in leukemic cells expressing wild type TP53 and induce p53-mediated apoptosis. In vitro studies with the combination demonstrated synergistic induction of apoptosis in AML cell lines and patient cells. Nutlin-3 and VPA co-treatment resulted in massive induction of p53, acetylated p53 and p53 target genes in comparison with either agent alone, followed by p53 dependent cell death with autophagic features. In primary AML cells, inhibition of proliferation by the combination therapy correlated with the CD34 expression level of AML blasts. To evaluate the combination in vivo, we developed an orthotopic, NOD/SCID IL2rγ(null) xenograft model of MOLM-13 (AML FAB M5a; wild type TP53) expressing firefly luciferase. Survival analysis and bioluminescent imaging demonstrated the superior in vivo efficacy of the dual inhibition of MDM2 and HDAC in comparison with controls. Our results suggest the concomitant targeting of MDM2-p53 and HDAC inhibition, may be an effective therapeutic strategy for the treatment of AML.

2. Small-molecule MDM2-p53 inhibitors: recent advances

Bian Zhang, Bernard T Golding, Ian R Hardcastle Future Med Chem. 2015;7(5):631-45.doi: 10.4155/fmc.15.13.

Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.

3. MDM2 Antagonists Counteract Drug-Induced DNA Damage

Anna E Vilgelm, Priscilla Cobb, Kiran Malikayil, David Flaherty, C Andrew Johnson, Dayanidhi Raman, Nabil Saleh, Brian Higgins, Brandon A Vara, Jeffrey N Johnston, Douglas B Johnson, Mark C Kelley, Sheau-Chiann Chen0, Gregory D Ayers0, Ann Richmond EBioMedicine. 2017 Oct;24:43-55.doi: 10.1016/j.ebiom.2017.09.016.Epub 2017 Sep 19.

Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.

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