PXD032239

PXD032239 is an original dataset announced via ProteomeXchange.

Title	A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Description	Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit the target and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. The oral route of administration is the option of choice in the clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4 deficient cancers. Here we outline structure- and property-guided approaches that led to the first orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
HostingRepository	PRIDE
AnnounceDate	2022-06-20
AnnouncementXML	Submission_2022-06-20_07:45:00.958.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vesna Vetma
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	dihydroxylated residue; 2-pyrrolidone-5-carboxylic acid (Gln); acetylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-11 11:10:55	ID requested
⏵ 1	2022-06-20 07:45:01	announced

Dataset with its publication pending

submitter keyword: PROTAC, TPD, SMARCA, oral bioavailability

Alessio Ciulli
contact affiliation	Professor of Chemical Structural Biology Director, Centre for Targeted Protein Degradation School of Life Sciences, University of Dundee JBC, Dow Street, Dundee DD1 5EH, UK
contact email	a.ciulli@dundee.ac.uk
lab head
Vesna Vetma
contact affiliation	University of Dundee
contact email	v.vetma@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032239
     1. Label: PRIDE project
     2. Name: A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo