Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential

Chemaly, Antoun El; Jaquet, Vincent; Cambet, Yves; Caillon, Aurélie; Cherpin, Ophélie; Balafa, Alexia; Krause, Karl‐Heinz; Demaurex, Nicolas

doi:10.1016/j.bbamcr.2022.119415

Cited by 5 publications

(14 citation statements)

References 44 publications

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“…However, these Hv1 inhibitors have multiple targets, and show low potency of Hv1 inhibition [ 262 ]. Newly discovered novel HV1 inhibitors have not been applied to the CNS [ 260 , 261 ]. Wang F et al utilized stereotactic injection of rabbit anti-Hv1 antibody, and they found that neutralization of Hv1 promoted myelin debris clearance by microglia [ 52 ].…”

Section: Clinical Translational Efforts Of Targeting Microglial Hv1 I...mentioning

confidence: 99%

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

Tang,

Wu,

et al. 2023

Aging and disease

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In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.

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Section: Clinical Translational Efforts Of Targeting Microglial Hv1 I...mentioning

confidence: 99%

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

Tang,

Wu,

et al. 2023

Aging and disease

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“…7,10,20,23,25−27 In tumor samples from human patients, increased expression of H V 1 correlated with poor disease prognosis. 24,26 Overexpression of H V 1 channels has been associated with disturbed pH balance and cancer development in several studies and has been proposed as a marker of malignancy in cancer. 11,23,27 Inhibition of H V 1 has been shown to reduce tumor cell proliferation, migration, along with cytokine and matrix metalloproteinase production.…”

Section: ■ Introductionmentioning

confidence: 99%

“…For the 30,31 (B) "H V 1 inhibitor flexible" compounds (HIFs); 32,33 (C) YHV98−4; 5 (D) PNX52429 and PNX61442. 24 screening, we used the 2GBI binding site of the openconformation model of hH V 1. 17 We performed two separate VS campaigns, a screening of the commercial library and a screening of our in-house compound library.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Recently, El Chemaly et al discovered two new potential H V 1 inhibitors, PNX52429 and PNX61442 (Figure D), by combining high-throughput screening (HTS) of a library of chemically diverse and commercially available compounds with compatible electrophysiological methods. These inhibitors provide potentially useful scaffolds with a favorable pharmacokinetic profile in vitro and in vivo that may be used to investigate the role of H V 1 inhibitors as therapeutics for the treatment of tumors and inflammatory diseases …”

Section: Introductionmentioning

confidence: 99%

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Identification of a Novel Structural Class of H_V1 Inhibitors by Structure-Based Virtual Screening

Piga,

Varga,

Feher

et al. 2024

J. Chem. Inf. Model.

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The human voltage-gated proton channel, hH V 1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of H V 1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hH V 1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structurebased virtual screening on an open structure of the human H V 1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hH V 1, with compound 13 showing strong block of the proton current with an IC 50 value of 8.5 μM. Biological evaluation of twenty-three additional analogs of 13 led to the discovery of six other compounds that blocked the proton current by more than 50% at 50 μM concentration. This allowed for an investigation of structure−activity relationships. The antiproliferative activity of the selected promising hH V 1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC 50 value of 9.0 and 8.1 μM, respectively. The identification of a new structural class of H V 1 inhibitors contributes to our understanding of the structural requirements for inhibition of this ion channel and opens up the possibility of investigating the role of H V 1 inhibitors in various pathological conditions and in cancer therapy.

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“…Multiple derivatives of the molecule 2-guanidinobenzimidazole (2GBI) were found to effectively block H V 1 from the intracellular side; however, it was 5-chloro-2-guanidinobenzimidazole (ClGBI) that raised the greatest interest as a research tool due to its highest affinity and much-improved ability to cross the membrane, thereby offering the possibility of extracellular applications [ 20 ]. Although several other blockers of H V 1 have been reported since then [ 15 , 16 , 17 , 21 ], ClGBI seems to remain the most frequently used tool to suppress H V 1 currents.…”

Section: Introductionmentioning

confidence: 99%

5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HV1 Channel

et al. 2023

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5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H+) channel (HV1, Kd ≈ 26 μM) and is widely used both in ion channel research and functional biological assays. However, a comprehensive study of its ion channel selectivity determined by electrophysiological methods has not been published yet. The lack of selectivity may lead to incorrect conclusions regarding the role of hHv1 in physiological or pathophysiological responses in vitro and in vivo. We have found that ClGBI inhibits the proliferation of lymphocytes, which absolutely requires the functioning of the KV1.3 channel. We, therefore, tested ClGBI directly on hKV1.3 using a whole-cell patch clamp and found an inhibitory effect similar in magnitude to that seen on hHV1 (Kd ≈ 72 μM). We then further investigated ClGBI selectivity on the hKV1.1, hKV1.4-IR, hKV1.5, hKV10.1, hKV11.1, hKCa3.1, hNaV1.4, and hNaV1.5 channels. Our results show that, besides HV1 and KV1.3, all other off-target channels were inhibited by ClGBI, with Kd values ranging from 12 to 894 μM. Based on our comprehensive data, ClGBI has to be considered a non-selective hHV1 inhibitor; thus, experiments aiming at elucidating the significance of these channels in physiological responses have to be carefully evaluated.

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Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential

Cited by 5 publications

References 44 publications

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

Identification of a Novel Structural Class of H_V1 Inhibitors by Structure-Based Virtual Screening

5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HV1 Channel

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Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential

Cited by 5 publications

References 44 publications

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

Identification of a Novel Structural Class of HV1 Inhibitors by Structure-Based Virtual Screening

5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HV1 Channel

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Identification of a Novel Structural Class of H_V1 Inhibitors by Structure-Based Virtual Screening