Triphenylphosphonium conjugation to a TRAP1 inhibitor, 2-amino-6-chloro-7,9-dihydro-8H-purin-8-one increases antiproliferative activity

Yang, Sujae; Yoon, Nam Gu; Park, Min-A; Yun, Jisu; Im, Jin Young; Kang, Byoung Heon; Kang, Soosung

doi:10.1016/j.bioorg.2022.105856

Cited by 8 publications

(4 citation statements)

References 26 publications

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“…MtHsp90 inhibitors have demonstrated the ability to effectively control cancer cell growth both in vitro and in vivo . There are several mtHsp90 inhibitors, such as gamitrinib, SMTIN-P01, SMTIN-C10, and DN401, that have been successfully designed to target mitochondria ( Table 1 ) ( 5 , 31 , 119 , 191 ). We have reviewed the research progress of mtHSP90 inhibitors for the treatment of relevant cancers according to the cancer types, which will be helpful for the development of therapeutic drugs for different cancers.…”

Section: Discussionmentioning

confidence: 99%

The development of cancers research based on mitochondrial heat shock protein 90

Xiang,

Liu,

Sun

et al. 2023

Front. Oncol.

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Mitochondrial heat shock protein 90 (mtHsp90), including Tumor necrosis factor receptor-associated protein 1 (TRAP1) and Hsp90 translocated from cytoplasm, modulating cellular metabolism and signaling pathways by altering the conformation, activity, and stability of numerous client proteins, and is highly expressed in tumors. mtHsp90 inhibition results in the destabilization and eventual degradation of its client proteins, leading to interference with various tumor-related pathways and efficient control of cancer cell development. Among these compounds, gamitrinib, a specific mtHsp90 inhibitor, has demonstrated its safety and efficacy in several preclinical investigations and is currently undergoing evaluation in clinical trials. This review aims to provide a comprehensive overview of the present knowledge pertaining to mtHsp90, encompassing its structure and function. Moreover, our main emphasis is on the development of mtHsp90 inhibitors for various cancer therapies, to present a thorough overview of the recent pre-clinical and clinical advancements in this field.

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Section: Discussionmentioning

confidence: 99%

The development of cancers research based on mitochondrial heat shock protein 90

Xiang,

Liu,

Sun

et al. 2023

Front. Oncol.

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“…Heat shock protein 90 (Hsp90) is a conserved molecular chaperone that mediates various cellular activities, such as cell transformation, proliferation, and survival under adverse conditions . As HSP90 is often overexpressed in prostate tumor tissue, it has emerged as a potential target for prostate cancer therapy. − Consequently, inhibiting the chaperones that control the HSP90 is a prospective therapeutic approach . It has strong antiproliferative and cytotoxic effects as well as the ability to degrade proteins .…”

Section: Opnps-mediated Pdt For Prostate Cancermentioning

confidence: 99%

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer

Ling,

Gu,

Liu

et al. 2023

ACS Mater. Au

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Radical prostatectomy is a primary treatment option for localized prostate cancer (PCa), although high rates of recurrence are commonly observed postsurgery. Photodynamic therapy (PDT) has demonstrated efficacy in treating nonmetastatic localized PCa with a low incidence of adverse events. However, its limited efficacy remains a concern. To address these issues, various organic polymeric nanoparticles (OPNPs) loaded with photosensitizers (PSs) that target prostate cancer have been developed. However, further optimization of the OPNP design is necessary to maximize the effectiveness of PDT and improve its clinical applicability. This Review provides an overview of the design, preparation, methodology, and oncological aspects of OPNP-based PDT for the treatment of PCa.

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“…To explore drug mitochondrial accumulation effects by attaching various TPP to the TRAP1 inhibitor, SJT109 ( 25 ) is further conjugated with tri( p -tolyl), tri( m -toyl), tri( o -tolyl), tri( p -methoxyphenyl), tri(cyclohexyl), and diphenylmethyl phosphine for the NTD targeting using a hexyl linker, which is better than propyl, octyl, decanyl, or dodecanyl in a previous study with PU-H71 and TPP . These subtle modifications of the phenyl ring of TPP marginally affected the in vitro inhibitory activity of the drugs toward TRAP1 NTD (FP assay: IC 50 = 1.6–1.8 μM).…”

Section: Development Of Orthosteric and Allosteric Trap1 Inhibitorsmentioning

confidence: 99%

Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1

Kang

2022

J. Med. Chem.

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Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecular chaperone modulating cellular metabolism and signaling pathways by altering the conformation, activity, and stability of numerous substrate proteins called clients. It exerts its chaperone function as an adaptive response to counter cellular stresses instead of maintaining housekeeping protein homeostasis. However, the stress-adaptive machinery becomes dysregulated to support the progression and maintenance of human diseases, such as cancers; therefore, TRAP1 has been proposed as a promising target protein for anticancer drug development. In this review, by collating recent reports on high-resolution TRAP1 structures and structure–activity relationships of inhibitors, we aimed to provide better insights into the chaperoning mechanism of the emerging drug target and to suggest an efficient strategy for the development of potent TRAP1 inhibitors.

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Triphenylphosphonium conjugation to a TRAP1 inhibitor, 2-amino-6-chloro-7,9-dihydro-8H-purin-8-one increases antiproliferative activity

Cited by 8 publications

References 26 publications

The development of cancers research based on mitochondrial heat shock protein 90

The development of cancers research based on mitochondrial heat shock protein 90

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer

Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1

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