PXD031880

PXD031880 is an original dataset announced via ProteomeXchange.

Title	Novel Eph receptor tyrosine kinase inhibitors block colorectal cancer cell growth
Description	Despite advances, treatment of unresectable colorectal cancer remains a clinical challenge and the incidence of this malignancy is increasing in individuals below the age of fifty. Integrated genomic, transcriptomic, proteomic, and mechanistic studies identified the tyrosine kinase receptors EphB2 and EphB4 as colorectal cancer drivers, and EphA2 activity as a cancer resistance mechanism to epidermal growth factor receptor and BRAF inhibitors. Reduction of EphB2 and EphB4 activity suppresses colorectal cancer cell growth and survival and is a potential target for colorectal cancer therapy. Here, we report the design and synthesis of two novel inhibitors, 1 and 3, that selectively bind with high affinity to A and B-type Eph receptor tyrosine kinases, inhibit A and B-type Eph tyrosine kinase activity, induce cell cycle arrest and confer a protracted state of growth reduction to colorectal cancer cells. 1 and 3 bind to EphA2 arresting the activation loop containing the conserved Asp-Phe-Gly (“DFG”)-motif in an inactive conformation and show a conserved hydrogen bond interaction with the so-called gatekeeper residue, the activation loop, alphaC helix, and hinge region of the kinase, typical of kinase inhibitors. These results demonstrate that pharmacological inhibition of Eph tyrosine kinase receptors is a valid therapeutic approach for the treatment of colorectal cancer.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:41:32.636.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Maria Reinecke
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-24 10:14:50	ID requested
1	2024-05-22 23:52:32	announced
⏵ 2	2024-10-22 06:41:38	announced	2024-10-22: Updated project metadata.

10.1002/chem.202203967;

Tr, ö, ster A, DiPrima M, Jores N, Kudlinzki D, Sreeramulu S, Gande SL, Linhard V, Ludig D, Schug A, Saxena K, Reinecke M, Heinzlmeir S, Leisegang MS, Wollenhaupt J, Lennartz F, Weiss MS, Kuster B, Tosato G, Schwalbe H, Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor. Chemistry, 29(23):e202203967(2023) [pubmed]

submitter keyword: Affinity pulldowns,Kinobeads, LC-MS/MS

Prof. Dr. Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
contact email	kuster@tum.de
lab head
Maria Reinecke
contact affiliation	Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
contact email	maria.reinecke@tum.de
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/2024/05/PXD031880

PRIDE project URI

• PRIDE
  1. PXD031880
     1. Label: PRIDE project
     2. Name: Novel Eph receptor tyrosine kinase inhibitors block colorectal cancer cell growth