PXD040208

PXD040208 is an original dataset announced via ProteomeXchange.

Title	Kinase Selectivity Profiling of anti-MRSA Diarylimidazoles in HEK293 Cells
Description	Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens and the results made publicly available through the Open Source Antibiotics (OSA) consortium. Of the 18 compounds tested (at 32 μg/mL), 15 showed >90% growth inhibition activity against MRSA alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized, tested against MRSA and structure-activity relationships identified. While potent, these compounds have moderate to high clearance rates and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency and solubility and slow clearance in rat hepatocytes. In this study, we used multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS) to study the human molecular targets of these phenotypically active compounds.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:26:01.069.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Aurora Cabrera
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-16 14:54:23	ID requested
1	2024-01-26 07:19:57	announced
⏵ 2	2024-10-22 06:26:02	announced	2024-10-22: Updated project metadata.

10.1021/acsinfecdis.3c00286;

Klug DM, Tse EG, Silva DG, Cao Y, Charman SA, Chauhan J, Crighton E, Dichiara M, Drake C, Drewry D, da Silva Emery F, Ferrins L, Graves L, Hopkins E, Kresina TAC, Lorente-Mac, í, as Á, Perry B, Phipps R, Quiroga B, Quotadamo A, Sabatino GN, Sama A, Sch, ä, tzlein A, Simpson QJ, Steele J, Shanu-Wilson J, Sj, ö P, Stapleton P, Swain CJ, Vaideanu A, Xie H, Zuercher W, Todd MH, . ACS Infect Dis, 9(12):2423-2435(2023) [pubmed]

submitter keyword: diarylimidazole, MIB-MS, kinases, HEK293, antimicrobials

Matthew H. Todd
contact affiliation	School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX
contact email	matthew.todd@ucl.ac.uk
lab head
Aurora Cabrera
contact affiliation	Department of Pharmacology at UNC Chapel Hill
contact email	Aurora_Cabrera@med.unc.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD040208

PRIDE project URI

• PRIDE
  1. PXD040208
     1. Label: PRIDE project
     2. Name: Kinase Selectivity Profiling of anti-MRSA Diarylimidazoles in HEK293 Cells