Delving into the Latest Updates on KW-2478 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

HSP90

Action

inhibitors

Mechanism

HSP90 inhibitors(Heat shock 90kDa proteins inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

Multiple Myeloma

Inactive Indication

Chronic Lymphocytic LeukemiaRefractory Multiple MyelomaRelapse multiple myeloma

Originator Organization

Kyowa Kirin Co., Ltd.

Active Organization

Kyowa Kirin Co., Ltd.

Inactive Organization

Kyowa Hakko Kirin Uk Ltd.

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC30H43ClN2O9

InChIKeyCKMGYWHSTADSIG-UHFFFAOYSA-N

CAS Registry819812-18-5

View All Structures (2)

The purpose of this study is to assess the safety and benefits of the investigational study drug, KW-2478, when given with bortezomib (Velcade®), a drug approved for the treatment of Multiple Myeloma (MM).
The primary objectives:
To establish the safety, tolerability, and recommended Phase II dose (RP2D) of KW-2478 in combination with bortezomib (Phase I);
To assess the overall response rate (ORR) when subjects with advanced MM are treated (Phase II).
The secondary objectives:
To characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of KW-2478 with bortezomib (Phase I only);
To evaluate for preliminary evidence of efficacy (Phase I);
To determine progression free survival (PFS) and duration of response of KW-2478 with bortezomib (Phase II).

Start Date01 Mar 2010

Sponsor / Collaborator

Kyowa Kirin Co., Ltd.

[+1]

NCT00457782

/ CompletedPhase 1

A Phase I, Open-Label, Dose-escalation, Multicentre Study of KW-2478 Administered as a Single Agent Intravenously in a Consecutive Dosing Schedule in Patients With Relapsed/Refractory Multiple Myeloma, Chronic Lymphocytic Leukaemia or B-cell Non-Hodgkin's Lymphoma

The aim of this study is to determine the safety, tolerability and dose-limiting toxicities of KW-2478 and to determine the Maximum Tolerated Dose and recommended Phase II dose for patients with relapsed/refractory MM, CLL or B-cell NHL.

Start Date01 Apr 2007

Sponsor / Collaborator

Kyowa Kirin Co., Ltd.

[+1]

100 Clinical Results associated with KW-2478

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100 Translational Medicine associated with KW-2478

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100 Patents (Medical) associated with KW-2478

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21

Literatures (Medical) associated with KW-2478

01 Jan 2024·Journal of Biological Chemistry

HSP90AB1 is a host factor that promotes porcine deltacoronavirus replication

Article

Author: Chen, Rui ; Cao, Sanjie ; Yan, Qigui ; Zhao, Qin ; Zhao, Yujia ; Xiao, Dai ; Du, Senyan ; Wen, Xintian ; Song, Daili ; Zhang, Luwen ; Li, Cheng ; Yuan, Jianlin ; Hu, Jingfei ; Han, Xinfeng ; Wen, Yiping ; Wu, Rui ; Huang, Xiaobo

Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus. It causes mortality in neonatal piglets and is of growing concern because of its broad host range, including humans. To date, the mechanism of PDCoV infection remains poorly understood. Here, based on a genome-wide CRISPR screen of PDCoV-infected cells, we found that HSP90AB1 (heat shock protein 90 alpha family class B1) promotes PDCoV infection. Knockdown or KO of HSP90AB1 in LLC-PK cells resulted in a significantly suppressed PDCoV infection. Infected cells treated with HSP90 inhibitors 17-AAG and VER-82576 also showed a significantly suppressed PDCoV infection, although KW-2478, which does not affect the ATPase activity of HSP90AB1, had no effect on PDCoV infection. We found that HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV. We further evaluated the interaction between N and HSP90AB1 and found that the C-tail domain of the N protein is the HSP90AB1-interacting domain. Further studies showed that HSP90AB1 protects N protein from degradation via the proteasome pathway. In summary, our results reveal a key role for HSP90AB1 in the mechanism of PDCoV infection and contribute to provide new host targets for PDCoV antiviral research.

05 Sep 2023·PNAS Nexus

Nucleoside analogs NM107 and AT-527 are antiviral against rubella virus

Article

Author: Cherry, Sara ; Miller, Jesse ; Sullivan, Kathleen E ; Perelygina, Ludmila ; Suppiah, Suganthi ; Schultz, David C ; Whig, Kanupriya ; Kamalia, Brinda ; Dittmar, Mark

AbstractRubella is a highly contagious viral infection that usually causes a mild disease in children and adults. However, infection during pregnancy can result in a fetal or newborn death or congenital rubella syndrome (CRS), a constellation of permanent birth defects including cataracts, heart defects, and sensorineural deafness. The live-attenuated rubella vaccine has been highly effective, with the Americas declared free of endemic rubella transmission in 2015. However, rubella remains a significant problem worldwide and the leading cause of vaccine-preventable birth defects globally. Thus, elimination of rubella and CRS is a goal of the World Health Organization. No specific therapeutics are approved for the rubella virus. Therefore, we set out to identify whether existing small molecules may be repurposed for use against rubella virus infection. Thus, we performed a high-throughput screen for small molecules active against rubella virus in human respiratory cells and identified two nucleoside analogs, NM107 and AT-527, with potent antiviral activity. Furthermore, we found that combining these nucleoside analogs with inhibitors of host nucleoside biosynthesis had synergistic antiviral activity. These studies open the door to new potential approaches to treat rubella infections.

05 Dec 2022·Journal of Biomolecular Structure and Dynamics

In silico identification of potential Hsp90 inhibitors via ensemble docking, DFT and molecular dynamics simulations

Article

Author: Rezvani, Saba ; Ebadi, Ahmad ; Razzaghi-Asl, Nima

The molecular chaperone heat shock protein 90 (Hsp90) has emerged as one of the most exciting targets for anticancer drug development and Hsp90 inhibitors are potentially useful chemotherapeutic agents in cancer. Within the current study, Hsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 structure query to find similar compounds (≥ 78%). Obtained small molecules (1-29) with defined similarity cut-off were docked into ensemble of Hsp90-α NTDs. Docked complexes were ranked on the basis of binding modes and Gibbs free energies as Hsp90 binders (cut-off point; ΔG_b ≤ -12 kcal/mol). Top-ranked compounds were subjected to energy decomposition analysis per residue of binding pocket via density functional theory (DFT) calculations in B3LYP level of theory. Subsequent MD simulations of the top-ranked complexes were performed for 100 ns to explore the stable binding modes during a reasonable period in explicit water. Results of molecular docking and intermolecular binding analysis indicated that H-bond, hydrophobic and salt bridge interactions were determinant forces in complex formation. Compounds 19 and 20 were well accommodated in binding pocket of Hsp90 via relatively varied conformations. It was revealed that Asn51 and Phe138 were key residues that interacted stably to 19 and 20. Although primary mechanism of action for proposed molecules are unknown and yet to be explored, results of the present study revealed key structural features for future structure-guided optimization toward potent inhibitors of Hsp90-α NTD. HighlightsHsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 based structure query to afford potential enzyme inhibitors 19 and 20.Quantum chemical calculations confirmed docking results and verified pivotal role of a conserved residues (Asn51, Leu103, Phe138 and Tyr139) in making effective hydrogen bonds.MD simulations of top-ranked docked derivatives revealed the achievement of stable binding modes with less conformational variation of 20 than 19 in the active site of Hsp90-α NTD.H-bond, hydrophobic contacts and salt bridge interactions were determinant forces in binding interactions of in silico hits.Resorcinol and isoxazole were important structural motifs of in silico hits in binding to the active site of Hsp90-α NTD.Communicated by Ramaswamy H. Sarma.

100 Deals associated with KW-2478

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Preclinical	Japan	Kyowa Kirin Co., Ltd.	13 May 2010
Refractory Multiple Myeloma	Preclinical	Philippines	Kyowa Kirin Co., Ltd.	01 Mar 2010
Refractory Multiple Myeloma	Preclinical	United States	Kyowa Kirin Co., Ltd.	01 Mar 2010
Refractory Multiple Myeloma	Preclinical	United Kingdom	Kyowa Kirin Co., Ltd.	01 Mar 2010
Chronic Lymphocytic Leukemia	Preclinical	United Kingdom	Kyowa Kirin Co., Ltd.	01 Apr 2007
Chronic Lymphocytic Leukemia	Preclinical	United Kingdom	Kyowa Hakko Kirin Uk Ltd.	01 Apr 2007
Relapse multiple myeloma	Preclinical	United Kingdom	Kyowa Hakko Kirin Uk Ltd.	01 Apr 2007
Relapse multiple myeloma	Preclinical	United Kingdom	Kyowa Kirin Co., Ltd.	01 Apr 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01063907 (Pubmed \| Med J Aust) Manual	Phase 1/2	Multiple Myeloma	95	KW-2478+bortezomib	(xvapygoejs) = yncxlzeuih djdvsxbyxk (rtgvgapfof ) View more	Positive	24 Oct 2017
NCT01063907 (CTgov)	Phase 1/2	Refractory Multiple Myeloma	95	KW-2478+Bortezomib (Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2)	ooaqvdiffu(mljrknzbcn) = cmcsdrkvaw qoqzyegxnz (ukmdshzoxh, htjgffwjia - lnskwnfpev) View more	-	05 Nov 2014
NCT01063907 (CTgov)	Phase 1/2	Refractory Multiple Myeloma	95	KW-2478+Bortezomib (Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2)	ooaqvdiffu(mljrknzbcn) = wbunxdpryr qoqzyegxnz (ukmdshzoxh, wofpfttxfm - vbvadzzolt) View more	-	05 Nov 2014