PXD067130

PXD067130 is an original dataset announced via ProteomeXchange.

Title	Discovery and development of a potent LIMK2 isoform-specific degrader
Description	The LIM kinases (LIMK1/2) are key mediators in the multi-step signaling cascades that regulate actin cytoskeleton dynamics via cofilin phosphorylation. Dysregulation of these pathways and overexpression of LIMKs are implicated in disease development, including cancer, Fragile X syndrome, and glaucoma. Positioned downstream of the Rac/CDC42 signaling pathways, LIM kinases are attractive drug targets. Here, we targeted the LIMKs with PROTACs to disrupt both catalytic and non-catalytic mediated functions. Despite employing a dual LIMK1/2 inhibitor warhead and high structural conservation between the two human LIM kinases, we discovered isoform-specific LIMK2 degradation. We developed initial PROTACs into a highly potent and selective LIMK2 degrader. Cell-based assays and structural comparisons suggested that isoform specificity was likely driven by favorable orientation bias and/or lysine accessibility, along with enhanced ternary complex formation. Finally, we comprehensively characterized the PROTAC as a chemical probe, which induces isoform-specific degradation, which can be challenging to achieve with conventional reversible inhibitors.
HostingRepository	PRIDE
AnnounceDate	2026-05-25
AnnouncementXML	Submission_2026-05-24_16:34:30.363.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thorsten Mosler
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-08 08:46:23	ID requested
⏵ 1	2026-05-24 16:34:31	announced

Azeez KRA, Saraswati H, Mosler T, Hanke T, Ho-Xuan H, Neder N, Sivashanmugam SA, Heinz M, Schwalm MP, Giuliani G, Rathore R, Kazi R, Kumar R, Mitrovic M, Prieto-Garcia C, Bailey HJ, Mathea S, Hummer G, Đ, iki, ć I, M, ü, ller S, Stolz A, Krause DS, Knapp S, Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader. ACS Chem Biol, 21(5):1158-1176(2026) [pubmed]

10.1021/acschembio.6c00137;

submitter keyword: LIMK, PROTAC

Stefan Knapp
contact affiliation	Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany German Cancer Consortium (DKTK) Mainz/Frankfurt, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
contact email	knapp@pharmchem.uni-frankfurt.de
lab head
Thorsten Mosler
contact affiliation	Goethe University Clinics Frankfurt
contact email	thorstenmosler@googlemail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067130
     1. Label: PRIDE project
     2. Name: Discovery and development of a potent LIMK2 isoform-specific degrader