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Global analysis of cancer cell responses to USP9X inhibition

ABSTRACT: Mass spectrometry-based 3X-FLAG-Ub-VS deubiquitinase (DUB) competition assay with cell extracts (DUB IP-MS) profiling MCF-7 cells with regard to specificity of WEHI-092, a selective inhibitor for USP9X. Sample key: #1-5 Untreated; #6-10 Ub-VS pre-treatment; #11-15 WEHI-092 treated (50 µM, 60 min).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Philipp Schenk

LAB HEAD: David Komander

PROVIDER: PXD074545 | Pride | 2026-04-09

REPOSITORIES: pride

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			Action	DRS
	USP9x_1.raw	Raw
	USP9x_10.raw	Raw
	USP9x_11.raw	Raw
	USP9x_12.raw	Raw
	USP9x_13.raw	Raw

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Publications

Global analysis of cancer cell responses to USP9X inhibition.

Schenk Philipp P Devine Shane M SM Cobbold Simon A SA Geoghegan Niall D ND Kyran Elizabeth L EL Ang Ching-Seng CS Alexandrovics Jack A JA Calleja Dale J DJ Multari Dylan H DH Vaibhav Vineet V Lu Bernadine G C BGC Klemm Theresa A TA Dagley Laura F LF Lowes Kym N KN Williamson Nicholas A NA Eichhorn Pieter J A PJA Ng Ashley P AP Feltham Rebecca R Komander David D

The EMBO journal 20260407 9

The ubiquitin-specific protease (USP) USP9X is a human deubiquitinase (DUB) with a large number of described targets and cellular roles. In cancer, USP9X is found as an oncogene or as a tumour suppressor depending on context, and its utility as a target for cancer therapy remains unclear. We here describe WEHI-092, a piperazine-based USP9X-specific small-molecule inhibitor, which binds to a unique region in the USP9X Fingers-subdomain, distinct from known DUB-inhibitor binding sites. Using prote ...[more]

PMID: 41946992

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Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor

Project description:Inhibition of the mitochondrial deubiquitinating enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson’s Disease and mitophagy-related disorders. We have integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small molecule containing a cyanopyrrolidine reactive group, USP30-I-1. The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells. Enzyme kinetics and Hydrogen Deuterium eXchange mass spectrometry (HDX-MS) infers that the inhibitor binds tightly to regions surrounding the USP30 catalytic cysteine and positions itself to form a binding pocket along the thumb and palm domains of the protein, thereby interfering its interaction with ubiquitin substrates. A comparison to a non-covalent USP30 inhibitor containing a benzosulfonamide scaffold revealed a slightly different binding mode closer to the active site Cys77, which may provide the molecular basis for improved selectivity towards USP30 against other members of the DUB enzyme family. Our results highlight advantages in developing covalent inhibitors, such as USP30-I-1, for targeting USP30 as treatment of disorders with impaired mitophagy.

2025-05-07 | PXD054041 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:Treatment of cancer cells MDA-MB-231 and MiaPaca2 with WEHI-092 (10 uM, 24 h) or FT709 (10 uM, 24 h). Sample key of raw file in ZIP folder: #1-6 MDA-MB-231 DMSO (untreated); #13-18 MDA-MB-231 FT709; #19-24 MDA-MB-231 WEHI-092; #25-30 MiaPaca2 DMSO (untreated); #37-42 MiaPaca2 FT709; #43-48 MiaPaca2 WEHI-092.

2026-04-09 | PXD074729 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:Global proteomics dataset for K-GG ubiquitin profiling of DLD-1 and MDA-MB-231 cells treated with the selective USP9X inhibitor WEHI-092 at 10 µM for 30 min, 6 h, and 24 h (and DMSO-treated control). This dataset also includes DLD-1 cells treated with FT671 (USP7 inhibitor) at 10 µM for 30 min and 6 h. Sample IDs: #1-5 Control 30 min DLD-1 #6-10 FT671 30 min DLD-1 #11-15 WEHI-092 30 min DLD-1 #16-20 Control 360 min DLD-1 #21-25 FT671 360 min DLD-1 #26-30 WEHI-092 360min DLD-1 #31-35 Control 30 min MDA-MB-231 #36-40 WEHI-092 30 min MDA-MB-231 #41-45 Control 360 min MDA-MB-231 #46-50 WEHI-092 360 min MDA-MB-231 #51-55 Control 24 h MDA-MB-231 #56-60 WEHI-092 24 h MDA-MB-231

2026-04-09 | PXD074673 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:K-GG ubiquitin profiling of DLD-1 and MDA-MB-231 cells treated with the selective USP9X inhibitor WEHI-092 at 10 µM for 30 min, 6 h, and 24 h (and DMSO-treated control). This dataset also includes DLD-1 cells treated with FT671 (USP7 inhibitor) at 10 µM for 30 min and 6 h. Sample IDs: #1-5 Control 30 min DLD-1 #6-10 FT671 30 min DLD-1 #11-15 WEHI-092 30 min DLD-1 #16-20 Control 360 min DLD-1 #21-25 FT671 360 min DLD-1 #26-30 WEHI-092 360min DLD-1 #31-35 Control 30 min MDA-MB-231 #36-40 WEHI-092 30 min MDA-MB-231 #41-45 Control 360 min MDA-MB-231 #46-50 WEHI-092 360 min MDA-MB-231 #51-55 Control 24 h MDA-MB-231 #56-60 WEHI-092 24 h MDA-MB-231

2026-04-09 | PXD075275 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:Global proteomics experiment using USP9X siRNA (and control) MDA-MB-231 cells with (10 µM, 24 h) and without USP9X inhibitor treatment using WEHI-092 and untreated (DMSO) control (P5448, see sample key). Global proteomics experiment profiling cancer cell lines treated with USP9X inhibitor WEHI-092 (10 µM, 24 h) and untreated (DMSO) control.P4971 1-5 UO-31 cells, untreatedP4971 6-10 UO-31 cells, WEHI-092P4971 11-15 A549 cells, untreatedP4971 16-20 A549 cells, WEHI-092P4971 21-25 DLD-1 cells, untreatedP4971 26-30 DLD-1 cells, WEHI-092P4971 41-45 OVCAR8 cells, untreatedP4971 46-50 OVCAR8 cells, WEHI-092P4971 51-55 SK-MEL-2 cells, untreatedP4971 56-60 SK-MEL-2 cells, WEHI-092P5080 11-15 HMEC-1 cells, untreatedP5080 16-20 HMEC-1 cells, WEHI-092

2026-04-09 | PXD062674 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:K-GG ubiquitin profiling of SK-MEL-2 and UO-31 cells treated with the selective USP9X inhibitor WEHI-092 at 10 µM for 30 min, 6 h, and 24 h (and DMSO-treated control). This dataset is the matched global quantitative proteomics data.Sample IDs:#1-5 Control 30 min UO-31#6-10 WEHI-092 30 min UO-31#11-15 Control 360 min UO-31#16-20 WEHI-092 360 min UO-31#21-25 Control 24 h UO-31#26-30 WEHI-092 24 h UO-31#31-35 Control 30 min SK-MEL-2#36-40 WEHI-092 30 min SK-MEL-2#41-45 Control 360 min SK-MEL-2#46-50 WEHI-092 360 min SK-MEL-2#51-55 Control 24 h SK-MEL-2#56-60 WEHI-092 24 h SK-MEL-2

2026-04-09 | PXD073798 | Pride

Small-Molecule Activity-Based Probe for Monitoring Ubiquitin 2 C‑Terminal Hydrolase (UCHL1) Activity in Live Cells and Zebrafish 3 Embryos

Project description:Many reagents have emerged to study the function of specific enzymes in vitro. On the other hand, target specific reagents are scarce or need improvement, allowing investigations of the function of individual enzymes in their native cellular context. Here we report the development of a target-selective fluorescent small-molecule activity-based DUB probe that is active in live cells and an in vivo animal model. The probe labels active ubiquitin carboxy-terminal hydrolase L1 (UCHL1), also known as neuron-specific protein PGP9.5 (PGP9.5) and Parkinson disease 5 (PARK5), a DUB active in neurons that constitutes 1 to 2% of the total brain protein. UCHL1 variants have been linked with neurodegenerative disorders Parkinson’s and Alzheimer’s diseases. In addition, high levels of UCHL1 also correlate often with cancer and especially metastasis. The function of UCHL1 activity or its role in cancer and neurodegenerative disease is poorly understood and few UCHL1-specific activity tools exist. We show that the reagents reported here are specific to UCHL1 over all other DUBs detectable by competitive activity-based protein profiling and by mass spectrometry. Our cell-penetrable probe, which contains a cyanimide reactive moiety, binds to the active-site cysteine residue of UCHL1 in an activity-dependent manner. Its use is demonstrated by the fluorescent labeling of active UCHL1 both in vitro and in live cells. We furthermore show that this probe can selectively and spatiotemporally report UCHL1 activity during the development of zebrafish embryos. Our results indicate that our probe has potential applications as a diagnostic tool for diseases with perturbed UCHL1 activity.

2020-09-18 | PXD021557 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:K-GG ubiquitin profiling of UO-31 cells treated with the selective USP9X inhibitor WEHI-092 at 10 µM for 30 min, 6 h, and 24 h (and DMSO-treated control). Sample IDs:#1-5 Control 30 min UO-31#6-10 WEHI-092 30 min UO-31#11-15 Control 360 min UO-31#16-20 WEHI-092 360 min UO-31#21-25 Control 24 h UO-31#26-30 WEHI-092 24 h UO-31

2026-04-09 | PXD073754 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:K-GG ubiquitin profiling of DLD-1 and MDA-MB-231 cells treated with the selective USP9X inhibitor WEHI-092 at 10 µM for 30 min, 6 h, and 24 h (and DMSO-treated control). This dataset also includes DLD-1 cells treated with FT671 (USP7 inhibitor) at 10 µM for 30 min and 6 h.Sample IDs:#1-5 Control 30 min DLD-1#6-10 FT671 30 min DLD-1#11-15 WEHI-092 30 min DLD-1#16-20 Control 360 min DLD-1#21-25 FT671 360 min DLD-1#26-30 WEHI-092 360min DLD-1#31-35 Control 30 min MDA-MB-231#36-40 WEHI-092 30 min MDA-MB-231#41-45 Control 360 min MDA-MB-231#46-50 WEHI-092 360 min MDA-MB-231#51-55 Control 24 h MDA-MB-231#56-60 WEHI-092 24 h MDA-MB-231

2026-04-09 | PXD073869 | Pride

Global analysis of cancer cell responses to USP9X inhibition

Project description:K-GG ubiquitin profiling of SK-MEL-2 cells treated with the selective USP9X inhibitor WEHI-092 at 10 µM for 30 min, 6 h, and 24 h (and DMSO-treated control). Sample IDs:#31-35 Control 30 min SK-MEL-2#36-40 WEHI-092 30 min SK-MEL-2#41-45 Control 360 min SK-MEL-2#46-50 WEHI-092 360 min SK-MEL-2#51-55 Control 24 h SK-MEL-2#56-60 WEHI-092 24 h SK-MEL-2

2026-04-09 | PXD073775 | Pride

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