Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors

Röhn, Till A.; Numao, Shin; Otto, H; Loesche, Christian; Thoma, Gebhard

doi:10.1080/17460441.2021.1948998

Cited by 10 publications

(23 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The only compound currently available on the market that interferes with LTB4 biosynthesis is Zileuton (Figure 12), a 5-LO inhibitor and a very weak inhibitor of LTB 4 biosynthesis [101]. It has only been approved in the United States for the treatment of asthma, and has some disadvantages, for example dose-limiting toxicity and unfavorable pharmacokinetic properties [102]. The development of an inhibitor specifically targeting LTA4H would be advantageous because it would allow the inhibition of LTB4 synthesis without affecting the biosynthesis of other lipids that depend on the upstream enzymes (e.g., 5-LO) [103].…”

Section: Inhibitorsmentioning

confidence: 99%

“…Researchers and the pharmaceutical industry have been actively searching for selective and potent LTA4H inhibitors for over ten years (see [103] for review). During this time, several inhibitors of LTA4H have been proposed, and five of those molecules have reached the early clinical development stage, although none of the clinical trials has targeted cancer patients [102]. Of these, only two, Acebilustat from Celtaxsys [104] and LYS006 from Novartis [105] (Figure 12), remain in active clinical development.…”

Section: Inhibitorsmentioning

confidence: 99%

“…All five proposed molecules inhibit both epoxide hydrolase and aminopeptidase catalytic activities of the enzyme [102].…”

Section: Inhibitorsmentioning

confidence: 99%

“…However, all the aminopeptidase-sparing LTA4H inhibitors proposed to date have shown very low potency in inhibiting the epoxide hydrolase activity of LTA4H when compared to general LTA4H inhibitors [78,85]. Because there are no solid data to date about the true physiological role of PGP, the physiological relevance of sparing the aminopeptidase function of LTA4H remains questionable [102].…”

Section: Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Teixeira

Sousa

2021

Pharmaceutics

View full text Add to dashboard Cite

Fighting cancer is one of the major challenges of the 21st century. Among recently proposed treatments, molecular-targeted therapies are attracting particular attention. The potential targets of such therapies include a group of enzymes that possess the capability to catalyze at least two different reactions, so-called multifunctional enzymes. The features of such enzymes can be used to good advantage in the development of potent selective inhibitors. This review discusses the potential of multifunctional enzymes as anti-cancer drug targets along with the current status of research into four enzymes which by their inhibition have already demonstrated promising anti-cancer effects in vivo, in vitro, or both. These are PFK-2/FBPase-2 (involved in glucose homeostasis), ATIC (involved in purine biosynthesis), LTA4H (involved in the inflammation process) and Jmjd6 (involved in histone and non-histone posttranslational modifications). Currently, only LTA4H and PFK-2/FBPase-2 have inhibitors in active clinical development. However, there are several studies proposing potential inhibitors targeting these four enzymes that, when used alone or in association with other drugs, may provide new alternatives for preventing cancer cell growth and proliferation and increasing the life expectancy of patients.

show abstract

Section: Inhibitorsmentioning

confidence: 99%

Section: Inhibitorsmentioning

confidence: 99%

“…All five proposed molecules inhibit both epoxide hydrolase and aminopeptidase catalytic activities of the enzyme [102].…”

Section: Inhibitorsmentioning

confidence: 99%

Section: Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Teixeira

Sousa

2021

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“… 35 LTB4 is involved in inducing anti-microbial factors, the release of inflammatory mediators, enhancing phagocytosis, and is also implicated in diseases in which neutrophils are strongly involved. 36 In allergic mucosal inflammation, LTB4 expression levels are significantly increased in Neutrophils, monocytes, and lymphocytes, suggesting a strong involvement in this process. 37 Some studies have confirmed that the expression of PRKCA is closely related to the inflammatory response of different systems, including the respiratory system and digestive system.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Combined with Network Pharmacology-Based Strategy to Reveal the Underlying Mechanism of Zhenhuang Submicron Emulsion in Treating Oropharyngeal Mucositis Complications of Radiation Therapy for Head and Neck Cancer

Chen¹,

Li²,

Jin³

et al. 2022

DDDT

View full text Add to dashboard Cite

Introduction Head and neck tumors account for more than 6% of all cancers. The primary treatment for tumors of the head and neck is radiation therapy, which can induce oropharyngeal mucositis as a side effect. At present, there is no widely available therapeutic for the treatment of oropharyngeal mucositis in clinical practice. Based on the traditional prescription Liushen Wan, the pathogenesis and pathology, we developed a new Chinese medicine prescription and made Zhenhuang submicron emulsion (ZHSE) spray, which has an efficacious therapeutic effect for oropharyngeal mucositis. However, its mechanism is unclear. Methods This research explored the mechanism behind the modulatory effects of ZHSE by a strategy of metabolomics and network pharmacology. Multivariate data analyses, including unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA), were performed. Potential biomarkers were identified depending on the mass-charge ratio of the selected compound. Statistical and pathway enrichment analysis was performed in the KEGG pathway database. Network pharmacology combining metabolomic analyses was conducted to illustrate the key targets and pathways. Results Critical metabolic pathways were investigated, 56f biomarkers were enriched and key metabolites such as linoleic acid, 9,10-epoxyoctadecenoic acid, acetoacetic acid and citric acid were identified. A complex network of “compound-target-potential metabolite” interactions was drawn to illuminate the regulation of chemical constituents on key metabolites. These findings manifest that ZHSE regulates endogenous metabolite disorders during the treatment of oropharyngeal mucositis by various constituents, interacting with multiple targets associated with inflammation and pain. Conclusion In this work, we determined several critical biomarkers and metabolic pathways and identified the possible regulatory mechanism by which ZHSE functions in the treatment of oropharyngeal mucositis. This study provides a new perspective on integrating metabolomics and network pharmacology for exploring improved therapy for head and neck tumors based on the traditional classic prescription of LSW.

show abstract

The Current Clinical Trial Landscape for Hidradenitis Suppurativa: A Narrative Review

Hunt,

Qian,

Olds

et al. 2023

Dermatol Ther (Heidelb)

View full text Add to dashboard Cite

Hidradenitis suppurativa (HS) is a skin disease resulting from chronic, recurrent inflammation around hair follicles, characterized by proinflammatory cytokines such as IL-1, IL-17, IL-23, and TNF-α. While adalimumab, a TNF-α targeting human IgG monoclonal antibody, is the only approved treatment for HS, there are many other therapies being investigated now targeting other key players in inflammatory pathways such as the cytokines listed above, C5a in the complement pathway, and Janus kinase (JAK). This review discusses current clinical trials for biologics and small molecules, procedures, and wound dressings undergoing study in hidradenitis suppurativa.

show abstract

Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors

Cited by 10 publications

References 83 publications

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

Metabolomics Combined with Network Pharmacology-Based Strategy to Reveal the Underlying Mechanism of Zhenhuang Submicron Emulsion in Treating Oropharyngeal Mucositis Complications of Radiation Therapy for Head and Neck Cancer

The Current Clinical Trial Landscape for Hidradenitis Suppurativa: A Narrative Review

Contact Info

Product

Resources

About