PXD075518-1

PXD075518 is an original dataset announced via ProteomeXchange.

Title	Light-Controlled Disruption of Cancer Cell Dormancy via Photoswitchable Stress Hormone Receptor Degraders
Description	Cancer cell dormancy is a key contributor to therapy resistance and disease relapse. The glucocorticoid receptor (GR), a major mediator of stress hormone signaling, has emerged as a central regulator of dormancy in non-lymphoid solid tumors, particularly lung cancer. However, systemic GR inhibition or degradation using conventional Proteolysis Targeting Chimeras (PROTACs) risks widespread on-target toxicity due to their constitutive activity. We hypothesized that integrating photoswitchable elements into PROTACs, termed photoPROTACs, would enable wavelength-specific, spatiotemporally precise modulation of GR degradation and dormancy-associated signaling pathways. Here, we synthesized a diverse series of photoPROTACs incorporating photoswitchable arylazotriazole or arylazopyrazole scaffolds, including previously unreported (OEt)2- and (NMe2)2-substituted photoswitches. Arylazopyrazole-based GR photoPROTACs bearing Me2- and (OEt)2 substituents exhibited near-quantitative photoisomerization (95% Z-isomer; 89% – 92% E-isomer), no photobleaching, and thermal half-lives in the range of 3−12.2 days in DMSO. Among them, KH-5-306 and KH-5-309 induced potent, specific, and reversible GR degradation in their thermodynamically stable E-isomeric form at low nanomolar concentrations, with markedly reduced activity in the Z-isomeric state. Transcriptomic profiling showed that E-KH-5-309 disrupts GR-driven dormancy-associated gene expression programs in a non-small lung cancer (NSLC) model, while the Z-isomer remains functionally inert. Our findings establish a framework for the rational design of photoswitchable PROTACs beyond GR and demonstrate their potential to achieve spatiotemporal control of stress hormone receptor signaling, enabling mechanistic insights into GR function and the targeted disruption of cancer cell dormancy.
HostingRepository	PRIDE
AnnounceDate	2026-05-21
AnnouncementXML	Submission_2026-05-21_13:57:59.753.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Robin Scheuplein
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-03-11 15:04:16	ID requested
⏵ 1	2026-05-21 13:58:00	announced

Dataset with its publication pending

submitter keyword: None

Prof. Dr.
contact affiliation	Department of Health Sciences and Technology (D-HEST) Institute Neurosciences, ETH Zurich
contact email	katharina.gapp@hest.ethz.ch
lab head
Robin Scheuplein
contact affiliation	Laboratory of Epigenetics and Neuroendocrinology, Institute for Neuroscience, Department of Health Science and Technology, ETH Zürich, Zürich 8057, Switzerland Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich 8057, Switzerland
contact email	robin.scheuplein@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD075518
     1. Label: PRIDE project
     2. Name: Light-Controlled Disruption of Cancer Cell Dormancy via Photoswitchable Stress Hormone Receptor Degraders