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Nervous System Diseases

Immune System Diseases

Skin and Musculoskeletal Diseases

Monoclonal antibody

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Disease Domain	Count

Immune System Diseases	1
Nervous System Diseases	1

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Monoclonal antibody	1

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LILRA4(Leukocyte immunoglobulin-like receptor subfamily A member 4)	1

AbstractAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. Although IL‐31, a type 2 helper T (Th2)‐derived cytokine, is important to the development of pruritus and skin lesions in AD, the blockade of IL‐31 signaling does not improve the skin lesions in AD. Oncostatin M (OSM), a member of IL‐6 family of cytokines, plays important roles in the regulation of various inflammatory responses through OSM receptor β subunit (OSMRβ), a common receptor subunit for OSM and IL‐31. However, the effects of OSM on the pathogenesis of AD remain to be elucidated. When AD model mice were treated with OSM, skin lesions were exacerbated and IL‐4 production was increased in the lymph nodes. Next, we investigated the effects of the monoclonal antibody (mAb) against OSMRβ on the pathogenesis of AD. Treatment with the anti‐OSMRβ mAb (7D2) reduced skin severity score in AD model mice. In addition to skin lesions, scratching behavior was decreased by 7D2 mAb with the reduction in the number of OSMRβ‐positive neurons in the dorsal root ganglia of AD model mice. 7D2 mAb also reduced the serum concentration of IL‐4, IL‐13, and IgE as well as the gene expressions of IL‐4 and IL‐13 in the lymph nodes of AD model mice. Blockade of both IL‐31 and OSM signaling is suggested to suppress both pruritus and Th2 responses, resulting in the improvement of skin lesions in AD. The anti‐OSMRβ mAb may be a new therapeutic candidate for the treatment of AD.

01 Apr 2017·European Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors

Q1 · MEDICINE

Article

Author: Hanada, Mitsuharu ; Sawa, Ayako ; Funakoshi, Yoko ; Masai, Hisao ; Taniyama, Chika ; Sawa, Masaaki ; Uno, Yuko ; Irie, Takayuki ; Asami, Tokiko

Cdc7 is a serine-threonine kinase and plays a conserved and important role in DNA replication, and it has been recognized as a potential anticancer target. Herein, we report the design, synthesis and structure-activity relationship of novel furanone derivatives as Cdc7 kinase inhibitors. Compound 13 was identified as a strong inhibitor of Cdc7 with an IC₅₀ value of 0.6 nM in the presence of 1 mM ATP and showed excellent kinase selectivity. In addition, it exhibited slow off-rate characteristics, which may offer advantages over known Cdc7 inhibitors in its potential to yield prolonged inhibitory effects in vivo. Compound 13 potently inhibited Cdc7 activity in cancer cells, and effectively induced cell death.

01 Dec 2015·Molecular Cancer Therapeutics

Abstract A180: Discovery of furanone derivatives as novel Cdc7 inhibitors with anti-tumor activity

Author: Masai, Hisao ; Sawa, Masaaki ; Irie, Takayuki ; Asami, Tokiko ; Funakoshi, Yoko ; Sawa, Ayako ; Uno, Yuko ; Taniyama, Chika

AbstractIntroduction>Cell cycle kinases have been recognized as potential anticancer targets, because loss of regulated cell cycle progression would lead to uncontrolled cell growth and development of cancer. Cdc7 kinase is involved in regulation of the cell cycle and plays important roles in DNA replication. Notably, inhibition of Cdc7 in cancer causes lethal S phase or M phase progression, whereas normal cells can survive, most likely through induction of cell cycle arrest at the DNA replication checkpoints. Therefore Cdc7 kinase has emerged as a promising therapeutic target for the treatment of cancers. Here we present a novel series of furanone derivatives with potent inhibitory effects on Cdc7 kinase.<Methods>To identify hit compounds that are insensitive or resistant to high ATP concentration, a high-throughput screening (HTS) was performed in the presence of 100 microM ATP which corresponds to 36-times higher than the Km value of ATP for Cdc7 kinase activity. To characterize inhibitors, ATP dependency and pre-incubation effects were examined. To determine the efficacy of Cdc7 inhibitors, phosphorylation of MCM2 protein in cells were analyzed by western blotting. Selected compounds were subjected to a kinase selectivity panel assay.<Results>Only a single hit compound was identified from the HTS, reflecting extremely low hit rate compared to that of other kinase targets in our past HTS. Subsequent hit to lead studies led to the identification of a novel furanone compound as a potential lead compound for further optimization study. Interestingly, these furanone derivatives showed slow-binding inhibition against Cdc7, and exhibited strong inhibitory activity for Cdc7 even in the presence of 1 mM ATP that was added after the pre-incubation of the kinase and compound. Notably this pre-incubation effect was not observed with other kinases tested. Detailed results using cancer cells will also be presented in this poster.Citation Format: Takayuki Irie, Tokiko Asami, Ayako Sawa, Chika Taniyama, Yoko Funakoshi, Yuko Uno, Hisao Masai, Masaaki Sawa. Discovery of furanone derivatives as novel Cdc7 inhibitors with anti-tumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A180.

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Pipeline

Pipeline Snapshot as of 29 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Daxdilimab ( LILRA4 )	Lupus Erythematosus, Cutaneous More	Phase 2
GNKS-356 ( TLR9 )	Psoriasis More	Discontinued
siRNA therapeutics(SBI Biotech Co., Ltd.)	Liver Cirrhosis More	Discontinued
KC-459 ( ASK1 x PKC )	Neoplasms More	Discontinued
GNKG-168 ( TLR9 )	Chronic Lymphocytic Leukemia More	Discontinued