PXD046903

PXD046903 is an original dataset announced via ProteomeXchange.

Title	Mass Spectrometry Methods and Mathematical PK/PD Model for Decision Tree-Guided Covalent Drug Development
Description	Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]; and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib); the most common plasma off-target, human serum albumin; three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.
HostingRepository	PRIDE
AnnounceDate	2025-01-23
AnnouncementXML	Submission_2025-01-22_21:45:14.921.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Md Amin Hossain
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	protein modification categorized by chemical process
Instrument	6220 Time-of-Flight LC/MS

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-13 06:58:43	ID requested
⏵ 1	2025-01-22 21:45:15	announced

Dataset with its publication pending

submitter keyword: Covalent Drug Discovery, ALS,Intact Protein Mass Spectrometry, PK/PD

Jeffrey N.
contact affiliation	Northeastern University
contact email	j.agar@northeastern.edu
lab head
Md Amin Hossain
contact affiliation	Harvard Medical School
contact email	mahossain@bwh.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046903
     1. Label: PRIDE project
     2. Name: Mass Spectrometry Methods and Mathematical PK/PD Model for Decision Tree-Guided Covalent Drug Development