RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer

Magna, Melinda; Hwang, Gyong Ha; McIntosh, Alec T.; Drews-Elger, Katherine; Takabatake, Masaru; Ikeda, Adam; Mera, Barbara; Kwak, Taekyoung; Miller, Philip; Lippman, Marc E.; Hudson, Barry I.

doi:10.1038/s41523-023-00564-9

Cited by 11 publications

(3 citation statements)

References 68 publications

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“…Oxidative stress also leads to the excessive formation of phenyl]-1H-imidazol-4-yl]phenoxy]-N,N-diethyl-1-propanamine; also called TTP488) suppresses metastasis in triple-negative breast cancer, and displayed a favorable safety profile in Phase II clinical trials. This RAGE-inhibitor strategy may lead to small-molecule-based therapeutical candidates for treating various oxidative-stress-mediated diseases, including AD [31,97].…”

Section: Discussionmentioning

confidence: 99%

“…There have been no FDA-approved RAGE inhibitor-based therapeutics to date because RAGE is a multi-ligand binding receptor, and achieving selectivity for RAGE binding is still a challenge. However, there are potentially useful therapeutics that are currently in clinical trials for treating cancers and neurological diseases (vide infra) [14,17,[31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress in Health and Disease

Reddy

2023

Biomedicines

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Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as Ne-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in Health and Disease

Reddy

2023

Biomedicines

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“…Consequently, drug studies targeting the RAGE, such as RAGE antagonists and blockers binding to RAGE ligands, show promise. The emerging research directions, such as the small molecule RAGE inhibitor TTP488 (azeliragon), are considered promising therapeutic approaches to inhibit RAGE-mediated signaling [30,201,202].…”

Section: Antioxidant Therapymentioning

confidence: 99%

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

Tang,

Buonfiglio,

Böhm

et al. 2024

Antioxidants

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Diabetic retinopathy (DR) represents a severe complication of diabetes mellitus, characterized by irreversible visual impairment resulting from microvascular abnormalities. Since the global prevalence of diabetes continues to escalate, DR has emerged as a prominent area of research interest. The development and progression of DR encompass a complex interplay of pathological and physiological mechanisms, such as high glucose-induced oxidative stress, immune responses, vascular endothelial dysfunction, as well as damage to retinal neurons. Recent years have unveiled the involvement of genomic and epigenetic factors in the formation of DR mechanisms. At present, extensive research explores the potential of biomarkers such as cytokines, molecular and cell therapies, antioxidant interventions, and gene therapy for DR treatment. Notably, certain drugs, such as anti-VEGF agents, antioxidants, inhibitors of inflammatory responses, and protein kinase C (PKC)-β inhibitors, have demonstrated promising outcomes in clinical trials. Within this context, this review article aims to introduce the recent molecular research on DR and highlight the current progress in the field, with a particular focus on the emerging and experimental treatment strategies targeting the immune and redox signaling pathways.

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Deciphering the landscape of triple negative breast cancer from microenvironment dynamics and molecular insights to biomarker analysis and therapeutic modalities

Tiwari,

Singh,

Sharma

et al. 2024

Medicinal Research Reviews

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Triple negative breast cancer (TNBC) displays a notable challenge in clinical oncology due to its invasive nature which is attributed to the absence of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor (HER‐2). The heterogenous tumor microenvironment (TME) of TNBC is composed of diverse constituents that intricately interact to evade immune response and facilitate cancer progression and metastasis. Based on molecular gene expression, TNBC is classified into four molecular subtypes: basal‐like (BL1 and BL2), luminal androgen receptor (LAR), immunomodulatory (IM), and mesenchymal. TNBC is an aggressive histological variant with adverse prognosis and poor therapeutic response. The lack of response in most of the TNBC patients could be attributed to the heterogeneity of the disease, highlighting the need for more effective treatments and reliable prognostic biomarkers. Targeting certain signaling pathways and their components has emerged as a promising therapeutic strategy for improving patient outcomes. In this review, we have summarized the interactions among various components of the dynamic TME in TNBC and discussed the classification of its molecular subtypes. Moreover, the purpose of this review is to compile and provide an overview of the most recent data about recently discovered novel TNBC biomarkers and targeted therapeutics that have proven successful in treating metastatic TNBC. The emergence of novel therapeutic strategies such as chemoimmunotherapy, chimeric antigen receptor (CAR)‐T cells‐based immunotherapy, phytometabolites‐mediated natural therapy, photodynamic and photothermal approaches have made a significant positive impact and have paved the way for more effective interventions.

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RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer

Cited by 11 publications

References 68 publications

Oxidative Stress in Health and Disease

Oxidative Stress in Health and Disease

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

Deciphering the landscape of triple negative breast cancer from microenvironment dynamics and molecular insights to biomarker analysis and therapeutic modalities

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