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AfBPP of Navtemadlin probes in MCF-7 cells

ABSTRACT: Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. The selectivity of this molecule is poorly understood. So we synthesised and validated two photoactivatable clickable probes of Navtemadlin. This data shows the proteins enriched upon treatment of MCF-7 cells with these probes.

INSTRUMENT(S): timsTOF HT

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Amrita Date

LAB HEAD: Anna Barnard

PROVIDER: PXD058036 | Pride | 2025-04-28

REPOSITORIES: Pride

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			Action	DRS
	AD8_A.zip	Other
	AD8_AMG_A.zip	Other
	AD8_AMG_B.zip	Other
	AD8_AMG_C.zip	Other
	AD8_AMG_D.zip	Other

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Publications

Affinity-based protein profiling of MDM2 inhibitor Navtemadlin.

Date Amrita A Wall Archie A Zhang Peiyu P Houghton Jack W JW Lu Jianan J Thomas Adam M AM Kovačič Tristan T Wilson Andrew J AJ Tate Edward W EW Barnard Anna A

Chemical science 20250312 16

Navtemadlin is a potent inhibitor of the p53-MDM2 protein-protein interaction, which plays a critical role in the proliferation of p53-wildtype tumours. Whilst Navtemadlin has progressed to multiple Phase III clinical trials in oncology, little has been disclosed regarding its selectivity for MDM2 in cells. Here, we report the synthesis and validation of photoactivatable clickable probes of Navtemadlin, and their application to <i>de novo</i> target discovery for Navtemadlin through affinity-bas ...[more]

PMID: 40115185

Similar Datasets

AfBPP of Navtemadlin probes in SJSA-1 cells

Project description:Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. The selectivity of this molecule is poorly understood. So we synthesised and validated two photoactivatable clickable probes of Navtemadlin. This data shows the proteins enriched upon treatment of SJSA-1 cells with these probes.

2025-04-28 | PXD058033 | Pride

Whole proteome experiment to validate treatment conditions in MCF-7 cells

Project description:Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. The selectivity of this molecule is poorly understood. So we synthesised and validated two photoactivatable clickable probes of Navtemadlin. This data shows the validation of treatment conditions through whole proteome proteomics experiments in order to ensure that the expression of key proteins such as MDM2 is uniform across conditions.

2025-04-28 | PXD058050 | Pride

Whole proteome experiment to validate treatment conditions in SJSA-1 cells

Project description:Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. The selectivity of this molecule is poorly understood. So we synthesised and validated two photoactivatable clickable probes of Navtemadlin. This data shows the validation of treatment conditions through whole proteome proteomics experiments in order to ensure that the expression of key proteins such as MDM2 is uniform across conditions.

2025-04-28 | PXD058047 | Pride

Whole proteome time course experiment in MCF-7 cells

Project description:Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. In this experiment, we test the effect of Navtemadlin treatment on protein expression in MCF-7 cells over the course of 24 h.

2025-04-28 | PXD058054 | Pride

Whole proteome time course experiment in SJSA-1 cells

Project description:Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. In this experiment, we test the effect of Navtemadlin treatment on protein expression in SJSA-1 cells over the course of 24 h.

2025-04-28 | PXD058053 | Pride

Comparison of SJSA-1 and MCF-7 whole proteome after Navtemadlin treatment

Project description:Navtemadlin is a potent small moeclule inhibitor of the p53-MDM2 protein-protein interaction, that is being tested in Phase II/III clinical trials for the treatment of cancer. In this experiment, we compare the whole proteme of MCF-7 and SJSA-1 cells following Navtemadlin treatment in order to gain an insight into the cause of the observed differences in the off-target profile of this molecule in the two cell lines.

2025-04-28 | PXD058081 | Pride

Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma [patients]

Project description:To investigate the effectiveness of p53 reactivation in treating glioblastoma, we conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) on 21 patients and determined achievable drug concentrations within tumor tissue and biological mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact, but patient relapse was observed. Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived glioblastoma (GBM) models. Navtemadlin induced partial tumor cell death as monotherapy, but combination with temozolomide enhanced apoptosis while sparing normal bone marrow cells in vitro. We additionally report upregulation of oligodendrocyte differentiation genes as an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicate that clinically achievable doses of navtemadlin exert pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy may be a route to more durable survival benefits.

2025-01-22 | GSE280951 | GEO

Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma

2025-01-22 | GSE280891 | GEO

A General Approach for Activity-based Protein Profiling of Oxidoreductases with Redox-differentiated Diarylhalonium Warheads

Project description:Activity-based protein profiling (ABPP) is a unique proteomic tool for measuring the activity of enzymes in their cellular context, which has been well established for enzyme classes exhibiting a characteristic nucleophilic residue (e.g. hydrolases). In contrast, the enzyme class of oxidoreductases has received less attention, as its members rely mainly on cofactors instead of nucleophilic amino acid residues for catalysis. ABPP probes have been designed for specific oxidoreductase subclasses, which rely on the oxidative conversion of the probes into strong electrophiles. Here we describe the development of ABPP probes for the simultaneous labeling of various subclasses of oxidoreductases. The probe warheads are based on hypervalent diarylhalonium salts, which show unique reactivity as their activation proceeds via a reductive mechanism resulting in aryl radicals leading to covalent labeling of liver proteins at several different amino acids in close proximity to the active sites. The redox potential of the probes can be tuned by isosteric replacement varyring the halonium central atom. ABPP experiments with liver using 16 probes differing in warhead, linker, and structure revealed distinct overlapping profiles and broad substrate specificities of several probes. With their capability of multi oxidoreductase subclass labeling – including rare examples for the class of reductases – and their unique design, the herein reported probes offer new opportunities for the investigation of the “oxidoreductome” of microorganisms, plants, animal and human tissues.

2025-05-06 | PXD043873 | Pride

Copper(I)-Nitrene Platform for Chemoproteomics Profiling of Methionine

Project description:Methionine plays a critical role in various biological and cell regulatory processes, making its chemoproteomic profiling indispensable for exploring its functions and potential in protein therapeutics. However, the advancement of methionine chemoproteomics is currently hindered by the scarcity of efficient labeling strategies. Methionine exhibits high kinetic reactivity and undergoes rapid oxidation due to the lower energy gap between Lowest Unoccupied Molecular Orbital (LUMO) and Highest Occupied Molecular Orbital (HOMO). Building on this unique high reactivity of methionine (Met), we introduce Copper(I)-Nitrene Platform (CuNiP) for robust, and selective labeling of Met to generate highly stable sulfonyl sulfimide conjugates under physiological conditions. We demonstrated the versatile proficiency of CuNiP to label methionine in a wide range of bioactive peptides, intact proteins (6.5-79.5 kDa) independent of molecular weight and 3D structures and proteins in complex cell lysate mixtures with varying payloads. Leveraging nitrene reactivity-based probes, we have discovered an array of new, previously undiscovered, ligandable proteins and sites harboring hyperreactive methionine within the landscape of the human proteome. Crucially, we employed CuNiP for live cell chemoproteomic profiling of methionine in breast (T47D) and prostate cancer (LnCap) cell lines, observing minimal cytotoxic effects and achieving dose-dependent labeling. Confocal imaging further revealed the spatial distribution of modified proteins within cell membrane, cytoplasm, and nucleus, underscoring the platform's potential in profiling the cellular interactome. This breakthrough, with its insights into live cell methionine labeling will deepen our understanding of protein biochemistry and also pioneers a transformative pathway in drug discovery.

2024-04-24 | PXD051224 | Pride