PXD060332-1

PXD060332 is an original dataset announced via ProteomeXchange.

Title	A Triple Action PROTAC for Wild-Type p53 Cancer Therapy
Description	Multiagent chemotherapy remains a cornerstone of cancer treatment but the side effects of each drug component can heighten toxicity and the pharmacologic challenges in achieving simultaneous cellular delivery can reduce efficacy and promote resistance. To address these limitations, we developed a Triple Action Proteolysis Targeting Chimera (TAPTAC) that targets three oncogenic mechanisms at once to maximally reactivate apoptosis in cancer. Our prototype, TAPTAC1, is a stapled peptide-small molecule chimera that transforms oncogenic HDM2 into a tumor suppressor by switching its mode of action from degrading p53 to a selected cancer target and by maximizing the synergistic p53 surge through further blockade of HDMX, another negative regulator of p53. TAPTAC1 is effective across a broad spectrum of cancers, with specificity of action driven by wild-type (WT) p53 status and pathway co-dependencies, as evidenced by multi-omics analyses. Importantly, TAPTAC1 activity is superior to combination treatment with the individual drug components and a small molecule PROTAC that targets HDM2 and BET proteins but not HDMX. Pharmacokinetic analyses guided dose-selection and in vivo testing demonstrated that TAPTAC1 was effective in mouse models of human osteosarcoma and leukemia, without evidence of gross toxicity. Quantitative proteomics confirmed elimination of BET proteins and robust p53 pathway activation in vitro and in vivo. Given the numerous drug modalities that depend on and synergize with p53 reactivation, and the preservation of WT p53 in ~90% of pediatric and ~50% of adult cancers, TAPTACs provide a drug development platform with the potential to achieve multiagent activity as single agents, overcoming limitations in the pharmacology, toxicology, efficacy, and clinical trial logistics of anti-cancer drug combinations.
HostingRepository	PRIDE
AnnounceDate	2026-01-12
AnnouncementXML	Submission_2026-01-11_16:24:13.773.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joao Paulo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue
Instrument	Orbitrap Eclipse; Orbitrap Astral; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-29 11:02:37	ID requested
⏵ 1	2026-01-11 16:24:14	announced

10.1016/j.xcrm.2025.102467;

Bird GH, Adhikary U, Schmidt MJ, Godes M, Tesar B, Camara CM, Paulo JA, Vidlak JF, DeAngelo TM, Marquez M, Gokhale P, Li R, Ho Sui SJ, Cameron MD, Gygi SP, Walensky LD, A triple-action PROTAC for wild-type p53 cancer therapy. Cell Rep Med, 6(12):102467(2025) [pubmed]

submitter keyword: BET proteins, cancer, BRD4,TAPTAC, degradation, MDM2/HDM2, PROTAC, MDMX/MDM4/HDMX, chimera, therapeutic, p53, stapled peptide

Loren D.Walensky
contact affiliation	Dana-Farber Cancer Institute 450 Brookline Avenue, Longwood Center 3217 Boston, MA 02215
contact email	loren_walensky@dfci.harvard.edu
lab head
Joao Paulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.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/2026/01/PXD060332

PRIDE project URI

• PRIDE
  1. PXD060332
     1. Label: PRIDE project
     2. Name: A Triple Action PROTAC for Wild-Type p53 Cancer Therapy