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+ [10]

Originator Organization

Arisyn Therapeutics Inc

Active Organization-

Inactive Organization

Arisyn Therapeutics Inc

Yungjin Pharm. Co., Ltd.F. Hoffmann-La Roche Ltd.

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC15H14O3

InChIKeyQZPQTZZNNJUOLS-UHFFFAOYSA-N

CAS Registry4707-32-8

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.

31 Dec 2024·OncoImmunology

β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers

Article

Author: Zhao, Ye ; Huang, Xiumei ; Fu, Yang-Xin ; Jiang, Shu ; Li, Xiaoguang ; Chen, Yaomin ; Chen, Xiang ; Tumbath, Soumya ; Zhou, Hao ; Jiang, Lingxiang ; Yin, Zhijun ; Lu, Tao ; Zhang, Taolan ; Zahid, Kashif Rafiq

NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. β-Lapachone (β-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD) and enhancing tumor immunogenicity. However, the interaction between β-Lap-mediated antitumor immune responses and neutrophils, novel antigen-presenting cells (APCs), remains unknown. This study demonstrates that β-Lap selectively kills NQO1-positive murine tumor cells by significantly increasing intracellular ROS formation and inducing DNA double strand breaks (DSBs), resulting in DNA damage. Treatment with β-Lap efficiently eradicates immunocompetent murine tumors and significantly increases the infiltration of tumor-associated neutrophils (TANs) into the tumor microenvironment (TME), which plays a crucial role in the drug's therapeutic efficacy. Further, the presence of β-Lap-induced antigen medium leads bone marrow-derived neutrophils (BMNs) to directly kill murine tumor cells, aiding in dendritic cells (DCs) recruitment and significantly enhancing CD8⁺ T cell proliferation. β-Lap treatment also drives the polarization of TANs toward an antitumor N1 phenotype, characterized by elevated IFN-β expression and reduced TGF-β cytokine expression, along with increased CD95 and CD54 surface markers. β-Lap treatment also induces N1 TAN-mediated T cell cross-priming. The HMGB1/TLR4/MyD88 signaling cascade influences neutrophil infiltration into β-Lap-treated tumors. Blocking this cascade or depleting neutrophil infiltration abolishes the antigen-specific T cell response induced by β-Lap treatment. Overall, this study provides comprehensive insights into the role of tumor-infiltrating neutrophils in the β-Lap-induced antitumor activity against NQO1-positive murine tumors.

01 Dec 2024·Computational and Structural Biotechnology Journal

Discovering novel Cathepsin L inhibitors from natural products using artificial intelligence

Article

Author: Wang, Hao ; Li, Qi ; Zhou, Si-Rui ; Zhu, Juan-Juan ; Kim, Hanna ; Yang, Jin-Kui

Cathepsin L (CTSL) is a promising therapeutic target for metabolic disorders. Current pharmacological interventions targeting CTSL have demonstrated potential in reducing body weight gain, serum insulin levels, and improving glucose tolerance. However, the clinical application of CTSL inhibitors remains limited. In this study, we used a combination of artificial intelligence and experimental methods to identify new CTSL inhibitors from natural products. Through a robust deep learning model and molecular docking, we screened 150 molecules from natural products for experimental validation. At a concentration of 100 µM, we found that 36 of them exhibited more than 50 % inhibition of CTSL. Notably, 13 molecules displayed over 90 % inhibition and exhibiting concentration-dependent effects. The molecular dynamics simulation on the two most potent inhibitors, Plumbagin and Beta-Lapachone, demonstrated stable interaction at the CTSL active site. Enzyme kinetics studies have shown that these inhibitors exert an uncompetitive inhibitory effect on CTSL. In conclusion, our research identifies Plumbagin and Beta-Lapachone as potential CTSL inhibitors, offering promising candidates for the treatment of metabolic disorders and illustrating the effectiveness of artificial intelligence in drug discovery.

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
Pancreatic adenocarcinoma metastatic	Phase 2	US	ArQule, Inc.	01 Jan 2005
Head and Neck Neoplasms	Phase 2	-	Arisyn Therapeutics Inc	-
Head and Neck Neoplasms	Phase 2	-	Arisyn Therapeutics Inc	-
Head and Neck Neoplasms	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Head and Neck Neoplasms	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Leiomyoma	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Leiomyoma	Phase 2	-	Arisyn Therapeutics Inc	-
Leiomyoma	Phase 2	-	ArQule, Inc.	-
Pancreatic Cancer	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
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	(otxoqanzxq) = Up to the 390 mg/m2 dose, ARQ 501 exhibited apparent linear pharmacokinetics, xypldlshch (zujmhajgtv ) View more	Positive	01 Jun 2005
ARVO2004	Not Applicable	Retinoblastoma	-	Beta-lapachone	yfntxdqhyy(etlhustgmj) = ucuzjfbyrn fcijokotrk (gvmissugya ) View more	-	01 May 2004
ARVO2004	Not Applicable	Retinoblastoma	-	Etoposide	dhrhatfzmp(veukblpwdn) = nnkibdnuua ltytunhiko (poddgfsqfb )	-	01 May 2004