PXD061151

PXD061151 is an original dataset announced via ProteomeXchange.

Title	Targeting transcription factors through an IMiD independent zinc finger domain
Description	Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells. To overcome this limit, we focused on a non-IMiD domain, SALL4 zinc finger cluster four (ZFC4). By combining ZFC4-DNA crystal structure and an in silico docking algorithm, in conjunction with cell viability assays, we screened several chemical libraries against a potentially druggable binding pocket, leading to the discovery of SH6, a compound that selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 treatment led to a significant 87% tumor growth inhibition of SALL4+ patient-derived xenografts and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors such as SALL4 in cancer.
HostingRepository	PRIDE
AnnounceDate	2025-06-23
AnnouncementXML	Submission_2025-06-22_16:06:45.731.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Junsu Kwon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-24 17:04:57	ID requested
⏵ 1	2025-06-22 16:06:46	announced

10.1038/s44321-025-00241-3;

Liu BH, Liu M, Radhakrishnan S, Dai MY, Jaladanki CK, Gao C, Tang JP, Kumari K, Go ML, Vu KAL, Kwon J, Seo HS, Song K, Tian X, Feng L, Tan JL, Melkonian AV, Liu Z, Wulf G, Arthanari H, Qi J, Dhe-Paganon S, Clohessy JG, Choong YK, Sivaraman J, Fan H, Tenen DG, Chai L, Targeting transcription factors through an IMiD independent zinc finger domain. EMBO Mol Med, 17(6):1393-1416(2025) [pubmed]

submitter keyword: Human, SALL4 degrader, HCC model, SH6

Li Chai
contact affiliation	Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
contact email	lchai@bwh.harvard.edu
lab head
Junsu Kwon
contact affiliation	Brigham and Women's Hospital
contact email	jkwon7@bwh.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/2025/06/PXD061151

PRIDE project URI

• PRIDE
  1. PXD061151
     1. Label: PRIDE project
     2. Name: Targeting transcription factors through an IMiD independent zinc finger domain