Cathepsin B inhibitors: Further exploration of the nitroxoline core

Sosič, Izidor; Mitrović, Ana; Knez, Damijan; Žugelj, Helena Brodnik; Štefane, Bogdan; Kos, Janko; Gobec, Stanislav

doi:10.1016/j.bmcl.2018.02.042

Cited by 26 publications

(35 citation statements)

References 39 publications

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“…15 NXQ was also considered as a potent and selective inhibitor of cathepsin B, hence reducing glioma tumor progression in vitro and in vivo, and a number of derivatives of NXQ were developed by using structure-based chemical synthesis in order to further improve its antitumor properties. 16,17 In this study, NXQ was found to suppress SCLC cell survival and induce SCLC cell apoptosis (Figures 1 and 2). These above indicated that it was conceivable that the widely used antibacterial agent NXQ might be tried for SCLC treatment in clinic.…”

Section: Discussionmentioning

confidence: 55%

“…In cholangiocarcinoma cells, NXQ also exhibited anticancer activity by inducing FoxM1 inhibition . NXQ was also considered as a potent and selective inhibitor of cathepsin B, hence reducing glioma tumor progression in vitro and in vivo, and a number of derivatives of NXQ were developed by using structure‐based chemical synthesis in order to further improve its antitumor properties . In this study, NXQ was found to suppress SCLC cell survival and induce SCLC cell apoptosis (Figures and ).…”

Section: Discussionmentioning

confidence: 93%

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Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Shi

2019

The Kaohsiung J of Med Scie

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The proto‐oncogene MDM2 is a nuclear‐localized E3 ubiquitin ligase, which promotes tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. In this study, the anti‐infective drug nitroxoline (NXQ) was screened out to effectively inhibit cell survival of small‐cell lung cancer (SCLC) cells, and induce SCLC cell apoptosis by suppressing antiapoptotic proteins (such as Bcl‐2 and MCL1) and upregulating proapoptotic protein Bim. In the mechanistic study, NXQ was found to downregulate MDM2 expression by inducing its proteasomal degradation, and thus upregulated p53 expression, which was a substrate protein of MDM2. Moreover, overexpression of MDM2 decreased the cytotoxicity of NXQ on SCLC cells. These results demonstrated that NXQ displayed anti‐SCLC activity by suppressing MDM2 expression, which suggested that anti‐infective NXQ had potential for SCLC treatment by targeting the MDM2/p53 axis.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 93%

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Shi

2019

The Kaohsiung J of Med Scie

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“…Moreover, absence of the ring nitro-gen did not impair inhibition of the endopeptidase activity of cathepsin B, while its exopeptidase activity was improved when compared to that of the compounds with the same substituents at other positions (Sosič et al, 2013). Additional structural modifications of the nitroxoline scaffold revealed that, for effective binding into the active site of cathepsin B, both rings are needed (Sosič et al, 2018). Also, in most cases, addition of small substituents at position 2 led to diminished inhibitory activity and an additional nitro group at position 7 also resulted in loss of cathepsin B inhibition (Sosič et al, 2018).…”

Section: Nitroxoline Derivativesmentioning

confidence: 92%

“…Nitroxoline derivatives were prepared with the aim of improving its activity against cathepsin B (Mirković et al, 2011;Sosič et al, 2013Sosič et al, , 2018Mitrović et al, 2017). Evaluation of new compounds with structural modifications on various positions of the nitroxoline scaffold revealed the structural requirements for cathepsin B inhibition (Mirković et al, 2011;Sosič et al, 2013Sosič et al, , 2018Mitrović et al, 2016Mitrović et al, , 2017. The nitro group at position 5 of nitroxoline was identified as essential for nitroxoline binding to cathepsin B, its absence resulting in loss of cathepsin B inhibition.…”

Section: Nitroxoline Derivativesmentioning

confidence: 99%

“…Additional structural modifications of the nitroxoline scaffold revealed that, for effective binding into the active site of cathepsin B, both rings are needed (Sosič et al, 2018). Also, in most cases, addition of small substituents at position 2 led to diminished inhibitory activity and an additional nitro group at position 7 also resulted in loss of cathepsin B inhibition (Sosič et al, 2018). Of all the nitroxoline derivatives prepared, the compound with a 2-(ethylamino)acetonitrile group at position 7 of the nitroxoline scaffold (compound 17, Fig.…”

Section: Nitroxoline Derivativesmentioning

confidence: 99%

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Nitroxoline: repurposing its antimicrobial to antitumor application

Mitrović

Kos

2019

Acta Biochim Pol

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Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.

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Synthesis of Novel Nitroxoline Analogs with Potent Cathepsin B Exopeptidase Inhibitory Activity

et al. 2020

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Nitroxoline, a well‐known antimicrobial agent, has been identified in several independent studies, and on different molecular targets, as a promising candidate to be repurposed for cancer treatment. One specific target of interest concerns cathepsin B, a lysosomal peptidase involved in the degradation of the extracellular matrix (ECM), leading to tumor invasion, metastasis and angiogenesis. However, dedicated optimization of the nitroxoline core is needed to actually deliver a nitroxoline‐based antitumor drug candidate. Within that context, 34 novel nitroxoline analogs were synthesized and evaluated for their relative cathepsin B inhibitory activity, their antiproliferative properties and their antimicrobial activity. More than twenty analogs were shown to exert a similar or even slightly higher cathepsin B inhibitory activity compared to nitroxoline. The implemented modifications of the nitroxoline scaffold and the resulting SAR information can form an eligible basis for further optimization toward more potent cathepsin B inhibitors in the quest for a clinical nitroxoline‐based antitumor agent.

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Cathepsin B inhibitors: Further exploration of the nitroxoline core

Cited by 26 publications

References 39 publications

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Nitroxoline: repurposing its antimicrobial to antitumor application

Synthesis of Novel Nitroxoline Analogs with Potent Cathepsin B Exopeptidase Inhibitory Activity

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