Delving into the Latest Updates on Nutlin-3 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

MDM2

Action-

Mechanism

MDM2-p53 interaction inhibitor(p53-binding protein Mdm-2 p53 interaction inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

Hoffmann-La Roche, Inc.

Active Organization-

Inactive Organization

Hoffmann-La Roche, Inc.

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC30H30Cl2N4O4

InChIKeyBDUHCSBCVGXTJM-YBFHJACQSA-N

CAS Registry548472-68-0

The tumor suppressor p53 activates transcription of the IER5 gene, which encodes an adapter protein of protein phosphatase PP2A. IER5 binds to both the B55 regulatory subunit of PP2A and PP2A's target proteins, facilitating PP2A/B55-catalyzed dephosphorylation of these proteins. Here, we show that IER5 functions as a positive regulator of p53 by inhibiting its ubiquitination, thereby increasing cellular p53 levels. Mechanistically, this effect of IER5 requires its nuclear localization and binding to both PP2A/B55 and the p53 ubiquitin E3 ligase MDM2. Importantly, IER5 fails to inhibit p53 ubiquitination in cells treated with the MDM2 inhibitor Nutlin-3. The IER5-PP2A/B55 complex dephosphorylates MDM2 at Ser166, leading to MDM2 ubiquitination and a reduction in nuclear MDM2. Altogether, our data provide evidence that IER5-PP2A/B55 regulates the nuclear balance between MDM2 and p53 via MDM2 dephosphorylation.

09 Apr 2025·Journal of the American Chemical Society

O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells

Article

Author: Li, Xinling ; Tian, Ruijun ; Ding, Ke ; Duan, Liping ; Wang, Zhen ; Huang, Weixue ; Ren, Xiaomei ; Zhao, Yujun ; Zhang, Zhi-Min ; Ma, Nan ; Zhang, Jinwei ; Zheng, Jiangnan ; Zhou, Yang ; Qiu, Xiaorong ; Zhang, Shijie ; Li, Lin ; Ling, Huan

Lysine residue represents an attractive site for covalent drug development due to its high abundance (5.6%) and critical functions. However, very few lysines have been characterized to be accessible to covalent ligands and perturb the protein functions, owing to their protonation state and adjacent steric hindrance. Herein, we report a new lysine bioconjugation chemistry, O-cyanobenzaldehyde (CNBA), that enables selective modification of the lysine ε-amine to form iso-indolinones under physiological conditions. Activity-based proteome profiling enabled the mapping of 3451 lysine residues and 85 endogenous kinases in live cells, highlighting its potential for modifying hyper-reactive lysines within the proteome or buried catalytic lysines within the kinome. Further protein crystallography and mass spectrometry confirmed that K271_ABL1 and K162_AURKA are covalently targetable sites in kinases. Leveraging a structure-based drug design, we incorporated CNBA into the core structure of Nutlin-3 to irreversibly inhibit the MDM2-p53 interaction by targeting an exposed lysine K94 on the surface of murine double minute 2. Importantly, we have demonstrated the potential application of CNBA as a lysine-recognized bioconjugation agent for developing new antibody-drug conjugates. The results collectively validate CNBA as a new selective and efficient modifying agent with broad applications for both buried and exposed lysine residues in live cells.

01 Apr 2025·PROTEOMICS

Monitoring Changes in the Levels of Newly Synthesized Proteins in Response to Nutlin‐3 Treatment

Article

Author: Hernychova, Lenka ; Vojtesek, Borek ; Way, Luke ; Vialaret, Jerome ; Ruidong, Li ; Mannaa, Atef Mahmoud ; Hupp, Ted

ABSTRACTDeveloping methodological approaches for discovering novel pathways is a key challenge in the life science research. Biological pathways are regulated—in higher eukaryotes—by a vast diversity of linear peptide motifs that mediate combinatorial specificity in signal transduction pathways. The E3 ubiquitin ligase component (MDM2) is such a protein that interacts with target proteins containing linear motifs such as p53. Drug leads, such as Nutlin‐3, that bind to the MDM2 hydrophobic pocket mimic p53 and can release p53 from MDM2 control and this can lead to cell death. However, these drug leads act allosterically, having agonist effects on MDM2's functions and there are other proteins whose steady state levels can be altered by Nutlin‐3. As cell density can alter the proliferation state of cell populations, we examined the impact of Nutlin‐3 on levels of newly synthesized proteins using pulse‐SILAC mass spectrometry. The data demonstrate that at differing cell densities or population‐wide proliferation rates, different newly synthesized proteins dominate the proteome landscape in a Nutlin‐3 dependent manner. These data further confirm that the cell state in a population of cells can in turn impact on the MDM2 signalling landscape. This methodology forms a blueprint for biomarker discovery using clinical samples that can detect changes in the synthesis rate of proteins in cell populations treated with specific agents. Broader implications highlight tools that can be used to study allosteric regulation of protein‐drug combinations.

100 Deals associated with Nutlin-3

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