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Last update 23 Jan 2025

STK39

Last update 23 Jan 2025

Basic Info

Synonyms

DCHT, serine threonine kinase 39, serine/threonine kinase 39

+ [6]

Introduction

May act as a mediator of stress-activated signals. Mediates the inhibition of SLC4A4, SLC26A6 as well as CFTR activities by the WNK scaffolds, probably through phosphorylation. Phosphorylates RELT.

Drugs associated with STK39

Rafoxanide

Target

OSR1 x STK39

Mechanism

OSR1 inhibitors [+1]

Active Org.

University of Birmingham

Originator Org.

University of Birmingham

Active Indication

Hypertension

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Stock 1S-14279

Target

STK39

Mechanism

STK39 inhibitors

Active Org.

Tokyo Medical & Dental University

Originator Org.

Tokyo Medical & Dental University

Active Indication

Hypertension

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

closantel

Target

OSR1 x STK39

Mechanism

OSR1 inhibitors [+1]

Active Org.

University of Birmingham

Originator Org.

University of Birmingham

Active Indication

Hypertension

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with STK39

100 Translational Medicine associated with STK39

0 Patents (Medical) associated with STK39

1,762

Literatures (Medical) associated with STK39

01 Mar 2025·European Journal of Pharmacology

Camk2n1 deficiency reduces the NaCl cotransporter activity through the CUL3/KLHL3/WNK4 complex in the kidney

Article

Author: Zhang, Zihao ; Zhang, Chong ; Zhang, Ya ; Jiang, Gengru

Calcium/calmodulin dependent protein kinase II inhibitor 1 (Camk2n1) is closely associated with a peak logarithm of odds score in quantitative trait loci for systolic blood pressure. Increased Camk2n1 mRNA expression has been specifically observed in the kidneys of hypertension mouse models. However, the precise role of Camk2n1 in the kidney remains unclear. We generated Camk2n1-/- mice using the CRISPR/Cas9 system. Compared to controls, Camk2n1-/- mice exhibited consistently lower systolic blood pressure across all measured time points. Deletion of Camk2n1 resulted in decreased apical labeling of phosphorylated and total thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule. NCC phosphorylation is regulated by activated SPAK/OSR1 kinases, which act downstream of With-No-lysine (K) kinase (WNK). In Camk2n1-/- mice, the elevated abundances of key components of the Cullin 3 (CUL3) RING ubiquitin ligase, including neddylated CUL3 and the adaptor Kelch-like protein 3, promoted proteasomal degradation of WNK4. In renal tissues, Camk2n1 deletion led to increased mRNA and protein levels of ubiquitin-like modifier-activating enzyme 3 (UBA3) and ubiquitin-conjugating enzyme E2 (UBE2M). Conversely, Camk2n1 overexpression in HEK293 cells resulted in decreased levels of UBA3 and UBE2M, along with reduced CUL3 neddylation. Treatment with MLN4924 effectively suppressed CUL3 hyperneddylation and restored WNK4 levels in the kidneys of Camk2n1-/- mice. In summary, Camk2n1 deletion lowers blood pressure, likely by promoting WNK4 degradation through dysregulated CUL3 RING ubiquitin ligase activity, which leads to decreased NCC activity.

01 Feb 2025·Molecular Carcinogenesis

NEK2 Promotes ESCC Malignant Progression by Inhibiting Cellular Senescence via the FOXM1/c‐Myc/p27 Signaling Pathway

Article

Author: Lv, Huilai ; Wang, Yaojie ; Tian, Ziqiang ; Zhao, Lianmei ; Wei, Sisi ; Zhang, Li ; Li, Jiachen ; Xu, Shi ; Dai, Suli

ABSTRACTNever in mitosis gene A (NIMA)‐related kinase 2 (NEK2) is a crucial serine‐threonine kinase involved in the process of cell mitosis. However, the precise relationship between NEK2 and esophageal squamous cell carcinoma (ESCC) remains inadequately understood. NEK2 expression in ESCC tissues was assessed through bioinformatics analysis, reverse transcription‐quantitative PCR (RT‐qPCR) and immunohistochemistry, revealing a correlation with ESCC patient prognosis. Cultured ESCC cells and human normal esophageal epithelial cells (HEEC) were used to investigate the effects of NEK2 knockdown on the development and progression of ESCC by integrated confluence algorithm, colony formation, wound‐healing, transwell, and ESCC xenograft tumor model, in vitro and in vivo. In ESCC tissues, NEK2 was found to be significantly upregulated, and its expression correlated with poor prognosis in ESCC patients. NEK2 may facilitate ESCC development by regulating cell proliferation, migration, and invasion. Additionally, results from in vivo experiments suggested that NEK2 knockdown can inhibit tumor growth. Moreover, forkhead box M1 (FOXM1) was identified as a potential downstream target of NEK2 in the regulation of ESCC, with its overexpression reversing the effects of NEK2 knockdown on ESCC. Mechanistic studies also indicated that NEK2 may promote the malignant progression of ESCC by inhibiting cellular senescence through the activation of the FOXM1/c‐Myc/p27 signaling pathways, which may provide a novel perspective for the management of ESCC.

01 Jan 2025·ACS Chemical Neuroscience

Discovery of Dual Targeting GSK-3β/HIV-1 Reverse Transcriptase Inhibitors as Neuroprotective Antiviral Agents

Article

Author: Puhl, Ana C. ; Riabova, Olga ; Makarov, Vadim ; Jones, Thane ; Raman, Renuka ; Kazakova, Elena ; Ekins, Sean ; Lane, Thomas R.

Glycogen synthase kinase-3 beta (GSK-3β or GSK-3B) is a serine-threonine kinase involved in various pathways and cellular processes. Alteration in GSK-3β activity is associated with several neurological diseases including Alzheimer's disease (AD), bipolar disorder, and rare diseases like Rett syndrome. GSK-3β is also implicated in HIV-associated dementia (HAD), as it is upregulated in HIV-1-infected cells and plays a role in neuronal dysfunction. Therefore, a small molecule that can inhibit both GSK-3β and HIV-1 reverse transcriptase could offer neuroprotective therapy for patients suffering from HIV-1. Despite this, there are no known GSK-3β inhibitors currently approved, thus prompting us to screen our panel of various antiviral compounds against this kinase to better understand its structure-activity relationship. We show for the first time that the approved drugs, etravirine and rilpivirine, possess GSK-3β activity (IC₅₀ 619 nM and 502 nM, respectively). We have also identified 3 lead molecules exhibiting IC₅₀ < 1 μM (11726169, 12326205, and 12326207), with compound 11726169 being the most potent in vitro GSK-3β inhibitor (IC₅₀ = 12.1 nM). We also describe the generation of machine learning models for GSK-3β inhibition and their validation with our data as an external test set and propose their use for the future optimization of such inhibitors.

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STK39

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