Delving into the Latest Updates on KW-2449 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

Bcr-Abl T315I inhibitors(BCR-ABL T315I mutation inhibitors), FGFR1 antagonists(Fibroblast growth factor receptor 1 antagonists), FLT3 inhibitors(Tyrosine-protein kinase receptor FLT3 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesImmune System Diseases

Active Indication-

Inactive Indication

acute leukemiaAcute Lymphoblastic LeukemiaAcute Myeloid Leukemia+ [3]

Originator Organization

Kyowa Hakko Kirin Pharma, Inc.

Active Organization-

Inactive Organization

Kyowa Kirin Co., Ltd.Kyowa Kirin, Inc. /Sancuso/Kyowa Kirin Pharmaceutical Development Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC20H20N4O

InChIKeyYYLKKYCXAOBSRM-UHFFFAOYSA-N

CAS Registry1000669-72-6

AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

01 Jan 2023·Frontiers in immunology

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis.

Article

Author: Xiao, Cheng ; Zhang, Mengxiao ; Cao, Xiaoxue ; Deng, Tingting ; Wang, Xing ; Xi, Xiaoyu ; Deng, Xiaobing ; Zhang, Guoqiang ; Wang, Qiong ; Xu, Yuan ; Ye, Qinbin

ObjectiveNecroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.MethodsThe plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis.ResultsThe plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1.ConclusionThese findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

01 Sep 2021·Endocrine, Metabolic & Immune Disorders - Drug TargetsQ4 · MEDICINE

Anti-Inflammatory Effect of KW-2449 on Autoimmune Encephalomyelitis: An Experimental Study on Mice

Q4 · MEDICINE

Article

Author: Di Fiore, Maria M. ; Miladi, Hosein ; Abbaspour, Allireza ; Hossein-Khannazer, Nikoo ; Azizi, Gholamreza ; Afraei, Sanaz ; Goudarzvand, Mahdi ; Bagheri, Yasser ; Ahmadabad, Hasan N. ; Tahmasebi, Saeed ; Panahi, Yaser ; Kamali, Ali N. ; Yazdani, Reza

Background:The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL, ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis of multiple sclerosis (MS). KW-2449 could modulate immune cells, but the immunomodulatory effects of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model.Methods: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution and compared with EAE and control mice. Following the treatment, histological analyses were performed on the brain and cerebellum to evaluate the pathological score. The gene expression levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA).Results:The results indicated that the clinical score, the infiltration of inflammatory cells and the demyelination in EAE mice treated with KW-2449 decreased significantly compared to control groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines, and MMP-2 in both brain mRNA expressions and serum levels of EAE mice.Conclusion:The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in the brain or in plasma and reduces EAE pathogenesis manifestation.

100 Deals associated with KW-2449

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
acute leukemia	Phase 2	US	Kyowa Kirin, Inc. /Sancuso/	01 Jun 2006
Acute Lymphoblastic Leukemia	Phase 2	US	Kyowa Kirin Pharmaceutical Development Ltd.	01 Jun 2006
Acute Lymphoblastic Leukemia	Phase 2	US	Kyowa Kirin, Inc. /Sancuso/	01 Jun 2006
Myelodysplastic Syndromes	Phase 2	US	Kyowa Kirin Pharmaceutical Development Ltd.	01 Jun 2006
Myelodysplastic Syndromes	Phase 2	US	Kyowa Kirin, Inc. /Sancuso/	01 Jun 2006
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 2	US	Kyowa Kirin, Inc. /Sancuso/	01 Jun 2006
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 2	US	Kyowa Kirin Pharmaceutical Development Ltd.	01 Jun 2006
Acute Myeloid Leukemia	Phase 2	US	Kyowa Kirin Co., Ltd.	-
Hematologic Neoplasms	Phase 2	-	Kyowa Kirin Co., Ltd.	-