PXD053334-1

PXD053334 is an original dataset announced via ProteomeXchange.

Title	Novel molecular glue degraders against broad range of myeloma and lymphoma cancer cell lines
Description	Targeted protein degradation of neosubstrates plays a crucial role in treating hematological cancers with IMiDs therapy. However, the inevitable drug resistance and hematological toxicities remain persistent challenges, limiting their clinical efficacy. Herein, we present the discovery of a lead degrader with a novel phthalazinone scaffold, termed I-4, which targets Ikaros family proteins. Through molecular dynamic-based drug design and unbiased proteomics analysis, we further developed a novel candidate, I-8, that significantly inhibited the growth of hematological cancer cells and induced the degradation of Ikaros family proteins and casein kinase 1α (CK1α) with nanomolar potency via a Cullin-CRBN dependent pathway. To further investigate the global protein degradation of neosubstrates induced by our degraders, we performed a quantitative proteomics analysis in cells treated with I-4/I-8, pomalidomide and CC-220. Additionally, to further explore the mechanisms underlying IMiDs resistance, we conducted proteomics analyses in cells with acquired resistance.
HostingRepository	iProX
AnnounceDate	2024-06-22
AnnouncementXML	Submission_2024-12-12_19:09:29.642.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zhiya Fan
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-24 00:01:55	ID requested
⏵ 1	2024-12-12 19:09:31	announced

Li P, Hu X, Fan Z, Sun S, Ran Q, Wei T, Wei P, Jiang Q, Yan J, Yang N, Jia C, Yang T, Mao Y, Cai X, Xu T, Zhao Z, Qian X, Qin W, Zhuang X, Fan F, Xiao J, Zheng Z, Li S, Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation. J Hematol Oncol, 17(1):77(2024) [pubmed]

submitter keyword: hematological cancer, molecular glue, rational drug design, neosubstrates, drug resistance

Weijie Qin
contact affiliation	National Center for Protein Science,Beijing
contact email	aunp_dna@126.com
lab head
Zhiya Fan
contact affiliation	National Center for Protein Science, Beijing
contact email	zyfan7@163.com
dataset submitter

iProX dataset URI