Delving into the Latest Updates on 5(R)-Hydroxytriptolide with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

5(R)-5-hydroxytriptolide, 5-Hydroxytriptolide, Hydroxytriptolide

+ [7]

Target

NOS2

Mechanism

NOS2 inhibitors(Nitric oxide synthase, inducible inhibitors), Immunostimulants

Therapeutic Areas

Immune System DiseasesInfectious DiseasesSkin and Musculoskeletal Diseases+ [1]

Active Indication

Rheumatoid ArthritisAcquired Immunodeficiency Syndrome

Inactive Indication-

Originator Organization

Shanghai Institute of Materia Medica Chinese Academy of Sci

Active Organization

Shanghai Institute of Materia Medica Chinese Academy of Sci

Shanghai Pharmaceuticals Holding Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (CN)

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Structure

Molecular FormulaC20H24O7

InChIKeyOKRSVUYYCJPECG-LFGMFVMYSA-N

CAS Registry583028-68-6

[Translation] A multicenter, randomized, double-blind, double-dummy, positive drug parallel controlled phase II clinical study on the efficacy and safety of Lei Teng Shu in the treatment of postmenopausal women with inadequate response to methotrexate and moderate to severe active rheumatoid arthritis

主要目的观察雷腾舒治疗甲氨蝶呤反应不足、绝经后、中重度活动性类风湿关节炎患者的疗效次要目的观察雷腾舒在上述受试者中安全性探索性目的探索雷腾舒的群体药代动力学（PopPK）特征、暴露-反应（E-R）关系

[Translation]

Primary objective: To observe the efficacy of Leitengshu in the treatment of postmenopausal patients with moderate to severe active rheumatoid arthritis who have insufficient response to methotrexate Secondary objective: To observe the safety of Leitengshu in the above subjects Exploratory objective: To explore the population pharmacokinetic (PopPK) characteristics and exposure-response (E-R) relationship of Leitengshu

Start Date22 Jun 2020

Sponsor / Collaborator

Shanghai Pharmaceuticals Holding Co., Ltd.

[+1]

NCT04084444 / CompletedPhase 2

Efficacy and Safety of T8 on Treating Chronic Abnormal Immune Activation in HIV/AIDS Patients: A Multicenter, Randomized, Double-blind, Dose-finding, Placebo-controlled Study

This is a multicenter, randomized, double-blind, dose-finding, placebo-controlled study in patients with chronic HIV infection and inadequate immune restoration treated with long-term highly active antiretroviral therapy (HAART). A total of 150 eligible subjects will be selected and randomized at a ratio of 1:1:1 into T8 0.5 mg QD, 1 mg QD, and placebo group, with background HAART unchanged, for 48 consecutive weeks.

Start Date25 Dec 2019

Sponsor / Collaborator

Shanghai Pharmaceuticals Holding Co., Ltd.

CTR20191397 / CompletedPhase 2

雷腾舒治疗HIV患者慢性异常免疫激活的有效性和安全性—多中心随机双盲、剂量探索安慰剂平行对照探索性临床试验

[Translation] Efficacy and safety of Leitengshu in the treatment of chronic abnormal immune activation in HIV patients: a multicenter, randomized, double-blind, dose-finding, placebo-controlled, parallel exploratory clinical trial

探索雷腾舒治疗艾滋病患者慢性异常免疫激活的有效性和安全性，为III期临床试验提供剂量选择依据。

[Translation]

Explore the effectiveness and safety of Leitengshu in treating chronic abnormal immune activation in AIDS patients and provide a basis for dose selection for Phase III clinical trials.

Start Date18 Dec 2019

Sponsor / Collaborator

Shanghai Pharmaceuticals Holding Co., Ltd.

[+1]

100 Clinical Results associated with 5(R)-Hydroxytriptolide

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100 Translational Medicine associated with 5(R)-Hydroxytriptolide

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100 Patents (Medical) associated with 5(R)-Hydroxytriptolide

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153

Literatures (Medical) associated with 5(R)-Hydroxytriptolide

01 Jan 2024·European Journal of Pharmacology

LLDT-8 ameliorates experimental autoimmune encephalomyelitis by mediating macrophage functions in the priming stage

Article

Author: Xu, Yun ; Bao, Xinyu ; Cao, Xiang ; Zhu, Li-Wen ; Dong, Xiaohong ; Hu, Yujie ; Li, Chenggang ; Xu, Lushan ; Shu, Xin ; Zhang, Zhi ; Liu, Pinyi ; Cao, Runjing

Multiple sclerosis (MS) is an inflammatory demyelinating disease in the central nervous system caused by T cell activation mediated by peripheral macrophages, resulting in severe neurological deficits and disability. Due to the currently limited and expensive treatments for MS, we here introduce an economic Chinese medicine extract, (5R)-5-Hydroxytriptolide (LLDT-8), which shows low toxicity and high immunosuppressive activity. We used the widely accepted mouse model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the immunosuppressive effect of LLDT-8 in vivo. Through the RNA-sequence analysis of peripheral macrophages in EAE mice, we discovered that LLDT-8 alleviates the symptoms of EAE by inhibiting the proinflammatory effect of macrophages, thereby blocking the activation and proliferation of T cells. In all, we found that LLDT-8 could be a potential treatment for MS.

01 Jan 2024·Chinese Journal of Natural Medicines

Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H: quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase

Article

Author: Xue, Jiayu ; Song, Jiangzhou ; Zhu, Ya ; Zhang, Bo ; Zou, Guiqing ; Ao, Lanjia ; Xu, Xiaowei ; Zhao, Zhou ; Hao, Haiping ; Sun, Huiyong

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.

01 Jan 2024·International Immunopharmacology

Comprehensive transcriptomic analyses identify the immunosuppressive effects of LLDT-8 in ART-treated SIV-infected rhesus macaques

Article

Author: Li, Taisheng ; Wei, Qiang ; Cao, Wei ; Lv, Tingxia ; Li, Xiuxia ; Lin, Ling ; Yang, Yang ; Wu, Yuanni ; Liu, Xiaosheng ; Li, Xiaodi ; Lu, Lianfeng ; Xue, Jing

BACKGROUNDChronic immune activation plays a significant role in the pathogenesis and disease progression of human immunodeficiency virus (HIV), and the existing interventions to address this issue are limited. In a phase II clinical trial, (5R)-5-hydroxytriptolide (LLDT-8) demonstrated promising potential in enhancing CD4⁺ T cell recovery. However, the therapeutical effects of LLDT-8 remained to be systemic explored.METHODSTo assess the treatment effects of LLDT-8, we conducted flow cytometry and RNA-seq analyses on eight Chinese rhesus monkeys infected with simian immunodeficiency virus (SIV). Additionally, we performed comprehensive transcriptomic analyses, including cross-sectional and longitudinal differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution analysis using peripheral blood mononuclear cell (PBMC) samples from 14-time points. These findings were further validated with RNA-seq analysis on patients who received LLDT-8 treatment, along with in vitro cellular experiments using human PBMCs.RESULTSFlow cytometry analysis revealed that LLDT-8 treatment significantly reduced the percentage of HLA-DR⁺CD38⁺CD8⁺ T cells in SIV-infected rhesus monkeys (P < 0.001). The cross-sectional and longitudinal analysis identified 2531 and 1809 DEGs, respectively. GSEA analysis indicated that LLDT-8 treatment led to significant downregulation of proliferation-related pathways, such as E2F targets, G2M checkpoint, and mitotic spindle pathways. WGCNA analysis identified two modules and 202 hub genes associated with CD8 activation levels. Deconvolution analysis showed a significant decrease in the proportion of CD8⁺ T cells and activated CD4⁺ T cells during LLDT-8 treatment. Gene ontology results demonstrated that the common DEGs between LLDT-8-treated patients and rhesus monkeys were primarily enriched in cell activation and cell cycle progression. Furthermore, in vitro cellular experiments validated the consistent impact of LLDT-8 in inhibiting proliferation, activation (HLA-DR and CD38 expression), exhaustion (PD-1 expression), and IFN-γ production in human CD4⁺ and CD8⁺ T cells.CONCLUSIONLLDT-8 exhibited notable efficacy in alleviating immune activation in both an in vivo animal model and in vitro human cell experiments. These findings suggest that LLDT-8 may hold potential as a drug for managing systemic immune activation associated with SIV/HIV infection, warranting further prospective clinical exploration.

100 Deals associated with 5(R)-Hydroxytriptolide

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12252

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	CN	Shanghai Institute of Materia Medica Chinese Academy of Sci	22 Jun 2020
Rheumatoid Arthritis	Phase 2	CN	Shanghai Pharmaceuticals Holding Co., Ltd.	22 Jun 2020
Acquired Immunodeficiency Syndrome	Phase 2	CN	Shanghai Pharmaceuticals Holding Co., Ltd.	18 Dec 2019
Acquired Immunodeficiency Syndrome	Phase 2	CN	Shanghai Institute of Materia Medica Chinese Academy of Sci	18 Dec 2019

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04084444 (Pubmed)	Phase 2	HIV Infections	149	(5R)-5-hydroxytriptolide 0.5 mg	(rcylsrulne) = TEAEs were reported in 41 of 46 (89.1%) participants in HT8 group, 43 of 51 (84.3%) in LT8, and 42 of 52 (80.7%) in PL group wjledhlvss (udkjmtjela ) View more	Positive	01 May 2023
				(5R)-5-hydroxytriptolide 1 mg