PXD055363

PXD055363 is an original dataset announced via ProteomeXchange.

Title	Quinoxaline analog selectively inhibits MAP3K1, blocks IKK and NPM1 phosphorylation, and sensitizes pancreatic cancer to gemcitabine
Description	Mitogen activated protein kinase kinase kinase 1 (MAP3K1), is involved in various cancer signaling networks including the NF-B, JNK, ERK, and p38 pathways. Functioning as a signaling kinase in these oncogenic pathways, MAP3K1 contributes to tumor growth and metastasis. Additionally, higher transcript levels of MAP3K1 in pancreatic patient tumors is associated with poorer 5-year survival, suggesting MAP3K1 is an attractive therapeutic target. Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKK), an important phosphorylation target of MAP3K1, was shown to be important in pancreatic cancer (PC) disease onset and progression. We previously reported a quinoxaline analog, Analog 84, which inhibits IKK phosphorylation and downstream NF-B pathway activation. To improve the metabolic stability and bioavailability of Analog 84, we developed 51-106, which moved -F atom to block a site of potential metabolism. Using a chemoproteomics approach for kinome profiling, KiNativTM, we show 51-106 selectively binds to MAP3K1 in an ATP-competitive manner. Follow up studies show 51-106 inhibits downstream phosphorylation of IKK and blocks TNF-induced MAP3K1-IKK-mediated NF-B activity. Treatment of PC cell lines MiaPaCa2 and PANC-1 with 51-106 inhibits cell growth and migration with low micromolar potency. Utilizing 51-106 as a tool to study MAP3K1 signaling, we use phosphoproteomics analysis to show MAP3K1 inhibition leads to a dose dependent decrease in NPM1 T199 phosphorylation, suggesting NPM1 may play a role in MAP3K1 signaling. We observe a dose-dependent S-phase arrest in cells treated with 51-106, potentially linking MAP3K1 inhibition to a dysfunctional DNA damage response. Consistent with this observation, in combination studies, 51-106 synergistically inhibited growth with gemcitabine in LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) cell lines in vitro and in KPC syngeneic orthotopic implantation mouse model of pancreatic cancer in vivo. Our data indicated that MAP3K1 inhibition may represent a promising therapeutic in PC. These findings underscore the need for further investigation into the molecular interactions and downstream effects of the MAP3K1-NPM1 signaling axis.
HostingRepository	PRIDE
AnnounceDate	2025-05-26
AnnouncementXML	Submission_2025-05-25_16:26:58.048.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akhilesh Pandey
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-29 10:29:06	ID requested
⏵ 1	2025-05-25 16:26:58	announced

10.3390/molecules30092001;

Boghean L, Singh S, Mangalaparthi KK, Kizhake S, Umeta L, Wishka D, Grothaus P, Pandey A, Natarajan A, A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network. Molecules, 30(9):(2025) [pubmed]

submitter keyword: NPM1,MAP3K1, NF-κB, IKKβ, quinoxaline, pancreatic cancer

Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
contact email	Pandey.Akhilesh@mayo.edu
lab head
Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905
contact email	pandey.akhilesh@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055363
     1. Label: PRIDE project
     2. Name: Quinoxaline analog selectively inhibits MAP3K1, blocks IKK and NPM1 phosphorylation, and sensitizes pancreatic cancer to gemcitabine