Delving into the Latest Updates on Beta Lapachone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [6]

Target

NQO1

Mechanism

NQO1 inhibitors(Quinone reductase 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication-

Inactive Indication

AdenocarcinomaAdvanced Malignant Solid NeoplasmFibrosis+ [9]

Originator Organization

Arisyn Therapeutics Inc

Active Organization-

Inactive Organization

Arisyn Therapeutics Inc

Yungjin Pharm. Co., Ltd.

ArQule, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC15H14O3

InChIKeyQZPQTZZNNJUOLS-UHFFFAOYSA-N

CAS Registry4707-32-8

Owing to the excellent stability, anticancer activity and immunogenicity, peroxynitrite (ONOO^-) has been gained enormous interests in cancer therapy. Nevertheless, precise delivery and control release of ONOO^- in tumors remains a big challenge. Herein, B16F10 cancer cell membrane/liposome hybrid membrane (CM-Lip) based biomimetic nanodrug with high-efficient tumor-homing and NIR-II laser controlled ONOO^- boost properties was designed for melanoma treatment. Briefly, NIR-II molecule IR1061, NO donor BNN6 and β-lapachone (Lapa) were firstly encapsulated in the heat-responsive palmitoyl phosphatidylcholine/cholesterol liposome, followed by fusion with B16F10 cell membrane (CM) to obtain biomimetic CM-Lip@(IR/BNN6/Lapa). The hybrid membrane-based nanodrug displayed excellent biocompatibility and melanoma-targeting efficiency. Upon 1064 nm laser irradiation, the mild photothermal effect of CM-Lip@(IR/BNN6/Lapa) firstly triggered the release of NO and Lapa, which subsequently catalyzed the quinone oxidoreductase 1 (NQO1) overexpressed in tumors to produce O₂^•-, finally caused intraturmal ONOO^- boost via cascade reaction. The boosted ONOO^- could effectively inhibit melanoma by ways of triggering mitochondrion-mediated apoptotic pathway, upregulating 3-nitrotyrosine expression, inducing DNA damage and inhibiting DNA repair enzyme expression of poly (ADP-ribose) polymerase 1 (PARP-1). Moreover, ONOO^- displayed excellent immunoactivation and immunomodulation activities by effectively inducing immunogenic tumor cell death, promoting dendritic cells maturation, increasing cytotoxic T lymphocytes expression and repolarizing M1-phenotype macrophages.

01 Feb 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency

Article

Author: Terburgh, Karin ; du Plessis, Charl ; Louw, Roan ; Goolab, Shivani ; Scholefield, Janine

Mitochondrial diseases, often caused by defects in complex I (CI) of the oxidative phosphorylation system, currently lack curative treatments. Human-relevant, high-throughput drug screening platforms are crucial for the discovery of effective therapeutics, with induced pluripotent stem cells (iPSCs) emerging as a valuable technology for this purpose. Here, we present a novel iPSC model of NDUFS4-related CI deficiency that displays a strong metabolic phenotype in the pluripotent state. Human iPSCs were edited using CRISPR-Cas9 to target the NDUFS4 gene, generating isogenic NDUFS4 knockout (KO) cell lines. Sanger sequencing detected heterozygous biallelic deletions, whereas no indel mutations were found in isogenic control cells. Western blotting confirmed the absence of NDUFS4 protein in KO iPSCs and CI enzyme kinetics showed a ~56 % reduction in activity compared to isogenic controls. Comprehensive metabolomic profiling revealed a distinct metabolic phenotype in NDUFS4 KO iPSCs, predominantly associated with an elevated NADH/NAD⁺ ratio, consistent with alterations observed in other models of mitochondrial dysfunction. Additionally, β-lapachone, a recognized NAD⁺ modulator, alleviated reductive stress in KO iPSCs by modifying the redox state in both the cytosol and mitochondria. Although undifferentiated iPSCs cannot fully replicate the complex cellular dynamics of the disease seen in vivo, these findings highlight the utility of iPSCs in providing a relevant metabolic milieu that can facilitate early-stage, high-throughput exploration of therapeutic strategies for mitochondrial dysfunction.

01 Jan 2025·Journal of Colloid and Interface Science

Triggering multiple modalities of cell death via dual-responsive nanomedicines to address the narrow therapeutic window of β-lapachone

Article

Author: Zhao, Yanjun ; Li, Yaru ; Li, Xin ; Liu, Yancheng ; Li, Yao ; Liu, Fang ; Wang, Zheng

The clinical translation of the anticancer drug β-lapachone (LAP) has been limited by the narrow therapeutic window. Stimuli-responsive anticancer drug delivery systems have gained tremendous attention in recent years to alleviate adverse effects and enhance therapeutic efficacy. Here, we report a dual pH- and enzyme-responsive nanocarrier to address the above issue of LAP. In detail, the epigallocatechin gallate (EGCG) and ferric ions were employed to engineer nanoscale ferric ion-polyphenol complexes where LAP was physically encapsulated therein. The coordination bond between Fe³⁺ and the catechol moiety of EGCG was sensitive to the low pH, enabling the triggered cargo release in the acidic endosomes/lysosomes. Afterward, the released LAP was activated by the overexpressed NAD(P)H: quinone oxidoreductase 1 (NQO1) and ferroptosis suppressor protein 1 (FSP1) in the tumor cells, followed by the generation of reactive oxygen species (ROS), and the induction of oxidative stress and apoptotic cell death. Meanwhile, EGCG could upregulate gasdermin E (GSDME), and ferric ions were involved in the Fenton reaction. Hence, EGCG and ferric ions could sensitize the toxicity of LAP through the induction of multiple cell death pathways (e.g., pyroptosis, ferroptosis, apoptosis, and necroptosis). The current work enlarged the LAP's therapeutic window via controlled cargo release and vehicle sensitization.

100 Deals associated with Beta Lapachone

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11948

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Phase 2	KR	Yungjin Pharm. Co., Ltd.	01 Jan 2013
Metabolic dysfunction-associated steatotic liver disease	Phase 2	KR	Yungjin Pharm. Co., Ltd.	01 Jan 2013
Squamous cell carcinoma of head and neck metastatic	Phase 2	US	-	01 Jul 2006
Leiomyosarcoma	Phase 2	US	-	01 Feb 2006
Adenocarcinoma	Phase 2	US	ArQule, Inc.	01 Jan 2005
Pancreatic adenocarcinoma metastatic	Phase 2	US	ArQule, Inc.	01 Jan 2005
Advanced Malignant Solid Neoplasm	Phase 2	US	-	01 Sep 2003
Head and Neck Neoplasms	Phase 2	-	Arisyn Therapeutics Inc	-
Leiomyoma	Phase 2	-	Arisyn Therapeutics Inc	-
Pancreatic Cancer	Phase 2	-	Arisyn Therapeutics Inc	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2005 Manual	Phase 1	Advanced Malignant Solid Neoplasm	18	ARQ 501	(qvmzakprmy) = Up to the 390 mg/m2 dose, ARQ 501 exhibited apparent linear pharmacokinetics, ziqhmeeqfa (utjmeojiue ) View more	Positive	01 Jun 2005
ARVO2004	Not Applicable	Retinoblastoma	-	Beta-lapachone	oivztqmeqe(otcauhaumz) = skhjqufuuk szxmtlmybo (yylbtnlgxi ) View more	-	01 May 2004
ARVO2004	Not Applicable	Retinoblastoma	-	Etoposide	hwpzaqyprb(qoarfnwuhp) = xacbxhhzin clglujdbzl (peqwevhsxy )	-	01 May 2004