JNK inhibitors(c-Jun N-terminal kinase inhibitors), MAPKAPK2 inhibitors(MAP kinase-activated protein kinase 2 inhibitors), p38α inhibitors(P38 α mitogen-activated protein kinase inhibitors)

Therapeutic Areas

Congenital DisordersEye DiseasesRespiratory Diseases+ [1]

Active Indication

Dystrophy, MacularInflammationPulmonary Disease, Chronic Obstructive

Inactive Indication

Diabetes Mellitus, Type 2

Originator Organization

Allinky Biopharma SL

Active Organization

Allinky Biopharma SL

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

100 Clinical Results associated with AIK-3

100 Translational Medicine associated with AIK-3

100 Patents (Medical) associated with AIK-3

Literatures (Medical) associated with AIK-3

14 Sep 2019·Experimental Lung ResearchQ4 · MEDICINE

Pseudomonas aeruginosa-derived flagellin stimulates IL-6 and IL-8 production in human bronchial epithelial cells: A potential mechanism for progression and exacerbation of COPD

Q4 · MEDICINE

Article

Author: Nakamoto, Keitaro ; Honda, Kojiro ; Watanabe, Masato ; Inui, Toshiya ; Wada, Hiroo ; Ishii, Haruyuki ; Sada, Mitsuru ; Nakamura, Masuo ; Takizawa, Hajime

Background and purpose of the study:Pseudomonas aeruginosa commonly colonizes the airway of patients with chronic obstructive pulmonary disease (COPD) and exacerbates their symptoms. P. aeruginosa carries flagellin that stimulates toll-like receptor (TLR)-5; however, the role of flagellin in the pathogenesis of COPD remains unclear. The aim of the study was to evaluate the mechanisms of the flagellin-induced innate immune response in bronchial epithelial cells, and to assess the effects of anti-inflammatory agents for treatment. Materials and methods: We stimulated BEAS-2B cells with P. aeruginosa-derived flagellin, and assessed mRNA expression and protein secretion of interleukin (IL)-6 and IL-8. We also used mitogen-activated protein kinases (MAPK) inhibitors to assess the signaling pathways involved in flagellin stimulation, and investigated the effect of clinically available anti-inflammatory agents against flagellin-induced inflammation. Results: Flagellin promoted protein and mRNA expression of IL-6 and IL-8 in BEAS-2B cells and induced phosphorylation of p38, ERK, and JNK; p38 phosphorylation-induced IL-6 production, while IL-8 production resulted from p38 and ERK phosphorylation. Fluticasone propionate (FP) and dexamethasone (DEX) suppressed IL-6 and IL-8 production in BEAS-2B cells, but clarithromycin (CAM) failed to do so. Conclusions:P. aeruginosa-derived flagellin-induced IL-6 and IL-8 production in bronchial epithelial cells, which partially explains the mechanisms of progression and exacerbation of COPD. Corticosteroids are the most effective treatment for the suppression of flagellin-induced IL-6 and IL-8 production in the bronchial epithelial cells.

01 Dec 2013·Biochemical JournalQ3 · BIOLOGY

Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production

Q3 · BIOLOGY

Article

Author: Menon, Manoj B. ; Lafera, Juri ; Gaestel, Matthias ; Tiedje, Christopher ; Konen, Timo ; Ronkina, Natalia ; Kotlyarov, Alexey

The p38 MAPK (mitogen-activated protein kinase)/MK2 [MAPKAP (MAPK-activated protein) kinase-2] signalling pathway is a major regulator of stress- and cytokine-induced gene expression at the transcriptional and post-transcriptional level. Using phosphoproteomics we identified the ER (endoplasmic reticulum)-associated ubiquitin-conjugating enzyme Ube2j1 as a potential substrate of MK2. We demonstrate that Ube2j1 is phosphorylated in a cytokine-, cytosolic stress- and LPS (lipopolysaccharide)-induced manner. The cytosolic stress-induced phosphorylation of Ube2j1 proceeds at Ser184, a site described previously to be phosphorylated in response to ER stress, which is located in a perfect MK2 consensus motif. The cytosolic stress-induced phosphorylation of Ube2j1, but not its ER-stress-induced phosphorylation is sensitive to p38/MK2 inhibitors and abrogated in MK2/MK3-deficient cells. In a pull-down assay we demonstrate the interaction of MK2 with Ube2j1 in HEK (human embryonic kidney)-293T cells. Furthermore, MK2 is able to phosphorylate recombinant Ube2j1, but not the S184A mutant in an in vitro kinase assay. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser184 upon p38-activating stress in vivo. However, ectopically expressed Ube2j1-S184A mutant displays ubiquitinating activity towards the model substrate ER-synthesized T-cell receptor-α similar to that of the wild-type protein. Interestingly, Ube2j1 is phosphorylated in response to LPS also in macrophages and contributes to MK2-dependent TNFα biosynthesis by a so far unknown mechanism.

PLOS ONEQ3 · CROSS-FIELD

Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis

Q3 · CROSS-FIELD

ArticleOA

Author: Serrano-Wu, Michael H ; Hubbard, Brian ; Ozcan, Lale ; Yurdagul, Arif ; Kasikara, Canan ; Tabas, Ira ; Kuriakose, George

Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.

100 Deals associated with AIK-3

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Preclinical	Spain	Allinky Biopharma SL	-
Dystrophy, Macular	Discovery	Spain	Allinky Biopharma SL	-
Inflammation	Discovery	Spain	Allinky Biopharma SL	-
Pulmonary Disease, Chronic Obstructive	Discovery	Spain	Allinky Biopharma SL	-

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