Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo‐controlled first‐in‐human study in healthy volunteers

Fernando, Disala; Dimelow, Richard; Gorey, Ciara; Zhu, Xinyi; Muya, C.; Parker, Connie; Wright, Wayne L.; Soleman, Sara; Walsh, Sarah; Crause, Madelein; Vlasakakis, Georgios; Guiney, William J.; Robertson, Nicola J.; Bergeal, Marylise; Cui, Yi; Krug, Alexander W.; Uings, Iain

doi:10.1111/bcp.15010

Cited by 2 publications

(2 citation statements)

References 13 publications

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“…The therapeutic potential of KMO inhibitors remains to be determined; however, a prior clinical trial of the KMO inhibitor GSK3335065 was conducted among healthy volunteers. While GSK3335065 rapidly increases kynurenine levels suggesting partial inhibition of KMO activity, the trial was terminated after a serious adverse event (SAE) occurred on the study and a relationship with the study drug could not be excluded ( 171 ).…”

Section: Targeting the Kynurenine Pathway For Anti-cancer Treatmentmentioning

confidence: 99%

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

León-Letelier,

Dou,

Vykoukal

et al. 2023

Front. Oncol.

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The kynurenine pathway (KP) and associated catabolites play key roles in promoting tumor progression and modulating the host anti-tumor immune response. To date, considerable focus has been on the role of indoleamine 2,3-dioxygenase 1 (IDO1) and its catabolite, kynurenine (Kyn). However, increasing evidence has demonstrated that downstream KP enzymes and their associated metabolite products can also elicit tumor-microenvironment immune suppression. These advancements in our understanding of the tumor promotive role of the KP have led to the conception of novel therapeutic strategies to target the KP pathway for anti-cancer effects and reversal of immune escape. This review aims to 1) highlight the known biological functions of key enzymes in the KP, and 2) provide a comprehensive overview of existing and emerging therapies aimed at targeting discrete enzymes in the KP for anti-cancer treatment.

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Section: Targeting the Kynurenine Pathway For Anti-cancer Treatmentmentioning

confidence: 99%

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

León-Letelier,

Dou,

Vykoukal

et al. 2023

Front. Oncol.

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“…GSK3335065 is a first in class, potent and selective inhibitor of KMO being developed for the treatment of acute pancreatitis. Administration of GSK3335065 reduces 3HK levels accompanied by an increase in l ‐Kyn and other products of alternative metabolic pathways (Fernando et al, 2022).…”

Section: Inhibitors Of Kmomentioning

confidence: 99%

Kynurenine‐3‐monooxygenase (KMO): From its biological functions to therapeutic effect in diseases progression

Chen

Zhang

Yang

et al. 2022

Journal Cellular Physiology

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Kynurenine‐3‐monooxygenase (KMO) is a mitochondrial enzyme involved in the eukaryotic kynurenine pathway (KP), which is the major catabolic route of tryptophan. KMO can convert the substrate kynurenine into the neurotoxin 3‐hydroxykynurenine and quinolinic acid, which promote the production of toxic metabolites and formation of free radical in the blood, while decrease the neuroprotective metabolite kynurenic acid. As a result of branch point, KMO is predicted as an attractive drug target for several diseases, especially neurodegenerative diseases, psychosis, and cancer. This review mainly pays attention to KMO structure and the research of mechanisms and functions, with a particular emphasis on the roles of KMO in the pathogenesis of various conditions. Furthermore, we also summarized important KMO inhibitors to supporting their effects on these diseases, indicating the prospect to find novel KMO inhibitors for diseases therapy.

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Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo‐controlled first‐in‐human study in healthy volunteers

Cited by 2 publications

References 13 publications

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

Kynurenine‐3‐monooxygenase (KMO): From its biological functions to therapeutic effect in diseases progression

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