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

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. 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.

INSTRUMENT(S): timsTOF HT

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Amrita Date

LAB HEAD: Anna Barnard

PROVIDER: PXD058081 | Pride | 2025-04-28

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	MCF-7_A.zip	Other
	MCF-7_B.zip	Other
	MCF-7_C.zip	Other
	MCF-7_D.zip	Other
	SJSA-1_A.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

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 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 experiment to validate treatment conditions in SJSA-1 cells

2025-04-28 | PXD058047 | 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

AfBPP of Navtemadlin probes 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 proteins enriched upon treatment of MCF-7 cells with these probes.

2025-04-28 | PXD058036 | Pride

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

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

Identification of the RNAs that bind with MDM2 by high-throughput RIP-seq in MDA-MB-231 and MCF-7 cells

Project description:The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops respectively and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 towards its tumor suppressing substrates, including P53, RBI and NFATI, etc.

2023-06-19 | GSE226511 | GEO

SynMyco transposon: engineering transposon vectors for efficient transformation of minimal genomes

Project description:This sample was prepared with a modified version of the Tn4001 transposon commonly used in Mycoplasmas. This transposon is described to work more efficiently in Mycoplasma agalactiae and, by extension, in other Mycoplasma species. This sample was prepared transforming this bacteria with a newly designed transposon named pMTnGm-SynMyco to test its efficiency by Transposon Sequencing tracked by deep sequencing.

2019-11-15 | E-MTAB-7425 | biostudies-arrayexpress